JP6367712B2 - Benzofuran compounds for the treatment of hepatitis C virus infection - Google Patents

Description

  The present invention relates to compounds useful as antiviral agents (particularly hepatitis C virus (HCV) inhibitors), pharmaceutical compositions comprising such compounds, and treatment of viral infections (eg HCV infection) and diseases associated with such infections or It relates to the use of such compounds in prevention.

  Worldwide, infection with HCV is a major cause of human liver disease. Chronic infections with HCV are associated with chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver failure. HCV is a member of the hepacivirus genus of the Flaviviridae family of RNA viruses that affect animals and humans. Its genome is an RNA chain of approximately 9.6-kilobases, one open reading frame encoding a polyprotein of approximately 3000 amino acids, untranslated adjacent to both the 5 'and 3' ends It consists of regions (5'- and 3'-UTR). This polyprotein serves as a precursor for at least 10 distinct viral proteins important for the replication and assembly of progeny virions. The composition of structural and nonstructural proteins in HCV polyprotein is: C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. The pathology of HCV infection primarily affects the liver, but the virus is found in other cell types in the body, including peripheral blood lymphocytes.

  HCV is the main causative agent of post-transfusion hepatitis and sporadic hepatitis. Infection with HCV is latent in a high proportion of chronically infected and infectious carriers who have not experienced clinical symptoms for many years. An estimated 170 million chronic carriers worldwide are at risk for developing liver disease.

  Due to the high variability of viral surface antigens, the presence of many viral genotypes, and the specific immunity demonstrated, the potential for the development of successful vaccines in the near future is low. α-interferon is widely used in the treatment of chronic HCV infection, either alone or in combination with ribavirin. However, HCV treatment with interferon has adverse side effects such as fatigue, fever, chills, headache, leukopenia, thrombocytopenia, psychiatric effects and related disorders, autoimmune and related disorders, and thyroid dysfunction There are many cases. Ribavirin, an inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), increases the efficacy of IFN-α in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of patients do not clear the virus with current standard treatment of interferon-α (IFN) and ribavirin.

  Recently, the introduction of pegylated interferon has improved both the initial response rate and sustained response rate, and the combination treatment with Peg-IFN and ribavirin has become the gold standard for treatment. However, the side effects associated with combination therapy continue. Ribavirin causes significant hemolysis in 10-20% of patients treated with current recommended doses, and this drug is teratogenic and fetal toxic. In addition, a significant number of patients do not respond to sustained reductions in viral load, and there is a clear need for more effective antiviral therapy for HCV infection.

  Many methods have been pursued to eradicate this virus. These methods include, for example, the application of antisense oligonucleotides or ribozymes to inhibit HCV replication. In addition, low molecular weight compounds that directly inhibit HCV proteins and prevent viral replication are considered an attractive strategy to control HCV infection. Among viral targets, NS3 / 4a protease / helicase and NS5b RNA-dependent RNA polymerase are considered to be the most promising viral targets for new drugs.

  Based on the above, there is a considerable need for new effective drugs to treat infection by HCV.

  The present invention relates to a benzofuran compound substituted at position 6 with a boron-containing moiety, a pharmaceutical composition comprising the above compound, a method for synthesizing such a compound, and the treatment and / or prevention of viral infections such as flavivirus infection (eg HCV infection) The use of such compounds in is provided.

The present invention relates to a compound of formula (I):

(Where:
R is selected from halogen, C _1-6 alkyl, alkoxy, —CN, —CF _3, —OC _6-10 aryl optionally substituted with halogen, and —O-heteroaryl optionally substituted with halogen. Independently selected from the group consisting of:
R ¹ is —C (O) OH, —C (O) NHR ⁵ or heterocyclyl;
R ² is C _1-6 alkyl, C _3-6 cycloalkyl, —C (H) F ₂ , —CF ₃ , or —OR ⁶ ;
R ³ is —S (O) ₂ R ⁷ or —C (O) R ⁷ ;
R ⁴ is
^{(a) B (R 8)} (R 9), XB (R 8) (R 9), OXB (R 8 (R 9), B - (R 8) (R 9) (R 12), XB (R ⁸ ) R ⁹ ) (R ¹² ), or heteroaryl substituted with Het optionally substituted with hydroxy or hydroxyalkyl; further halogen, C _1-6 alkoxy, —C (H) F ₂ , -CF ₃ , C _1-6 alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C (O) NH ₂ , -C (O) OH, -C (O) NHR ⁵ , -S (O) ₂ R ⁶ , -S (O) ₂ NH ₂ , -CN, -OCF ₃ , -OR ^6, -NR ¹⁰ R ¹¹ , -NHC (O) R ¹⁰ , C _3-6 cycloalkyl, and independently from the group consisting of heterocyclyl Heteroaryl optionally substituted with one or more selected substituents;
^{(b) B (R 8)} (R 9), XB (R 8) (R 9), OXB (R 8 (R 9), B - (R 8) (R 9) (R 12), XB (R ⁸ ) R ⁹ ) (R ¹² ), or C _6-10 aryl substituted with Het optionally substituted with hydroxy or hydroxyalkyl; further halogen, C _1-6 alkoxy, —C (H _{) F 2, -CF 3, C} 1-6 alkyl, hydroxy, hydroxyalkyl, _{aminoalkyl, -C (O) NH 2,} -C (O) OH, -C (O) NHR 5, -S (O) ₂ R ⁶ , —S (O) ₂ NH ₂ , —CN, —OCF ₃ , —OR ⁶ , —NR ¹⁰ R ¹¹ , —NHC (O) R ¹⁰ , C _3-6 cycloalkyl, and heterocyclyl C _6-10 aryl optionally substituted with one or more substituents independently selected from:
(c) Halogen, C _1-6 alkoxy, -C (H) F ₂ , -CF ₃ , C _1-6 alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C (O) NH ₂ , -C (O) OH, -C (O) NHR ⁵ , -S (O) ₂ R ⁶ , -S (O) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC (O) Het optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁰ , C _3-6 cycloalkyl, and heterocyclyl;
Het is a 5- or 6-membered monocyclic heterocycle or an 8- to 11-membered bicyclic heterocycle system, any ring of which is either saturated, partially saturated or unsaturated, and monocyclic Optionally benzo-fused, or optionally spiro-fused, where each Het is one or more carbon atoms and one boron atom and one or more oxygen atoms; Consisting of one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms,
R ⁵ is hydrogen, C _1-6 alkyl, hydroxy, or —OR ⁶ ;
R ⁶ is C _1-6 alkyl or C _3-6 cycloalkyl;
R ⁷ is C _1-6 alkyl, hydroxyalkyl, or aminoalkyl;
R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ or R ⁸ , R ⁹ , and R ¹² are the boron atom to which they are attached. Taken together form a 5- to 14-membered ring, which contains a carbon atom and optionally one or more heteroatoms that may be N or O; the ring is C _1-6 alkyl, hydroxyalkyl , Aminoalkyl, amino, oxo, C (O) OH, C (O) OXOR ¹³ , C (O) N (R ¹⁰ ) (R ¹¹ ), N (R ¹⁰ ) (R ¹¹ ), and C _3-6 Cycloalkyl, each independently selected from the group consisting of hydroxy, amino, halogen, C (O) OH, C (O) N (R ¹⁰ ) (R ¹¹ ), and N (R ¹⁰ ) (R ¹¹ ) Optionally substituted with one or more substituents which may be optionally substituted with one or more substituents independently selected from the group consisting of:
R ¹⁰ and R ¹¹ are each independently hydrogen or C _1-6 alkyl;
R ¹³ is alkoxy;
X is alkylene or -O alkylene, where alkylene is halogen, C _1-6 alkoxy, -C (H) F ₂ , -CF ₃ , C _1-6 alkyl, hydroxy, hydroxyalkyl, aminoalkyl, _{-C (O) NH 2, -C} (O) OH, -C (O) NHR 5, -S (O) 2 R 6, -S (O) 2 NH 2, -CN, -OCF 3, -OR ⁶ , optionally substituted with one or more substituents independently selected from the group consisting of —NR ¹⁰ R ¹¹ , —NHC (O) R ¹⁰ and C _3-6 cycloalkyl;
m is 1, 2, or 3)
Or a pharmaceutically acceptable salt thereof.

The term “alkyl” refers to a straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms, unless otherwise specified. For example, C _1-6 alkyl means a straight or branched alkyl containing at least 1 and at most 6 carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl, and 1,1-dimethylpropyl is mentioned.

  The term “alkylene” refers to a straight or branched divalent hydrocarbon group, preferably having from 1 to 10 carbon atoms, unless otherwise specified. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

The term “alkoxy” refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, C _1-6 alkoxy means a straight or branched alkoxy group containing at least 1 and at most 6 carbon atoms. Examples of “alkoxy” as used herein include, but are not limited to, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2-oxy, Examples include 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.

  The term “halogen” or “halo” refers to a fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br) or iodine (iodo, I) atom.

  The term “hydroxy” refers to a group or substituent of the formula OH.

  The term “cycloalkyl” refers to a saturated cyclic group containing from 3 to 6 carbon ring atoms (unless otherwise specified). Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

  The term “aryl” refers to a carbocyclic aromatic moiety (eg, phenyl or naphthyl) containing the specified number of carbon atoms, particularly 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl, and the like. Unless otherwise indicated, the term “aryl” includes 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthate. Each possible positional isomerism of an aromatic hydrocarbon group such as lysinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl The body is also included. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl, and the like.

  The term “heteroaryl” refers to 5 to 20 carbon atoms (preferably 5 to 5), wherein one or more (preferably 1 to 4) ring carbons are each substituted with a heteroatom such as N, O, and S. Refers to a 5, 6, 8, 9 or 10 membered carbocyclic or bicyclic aromatic monocyclic or polycyclic ring group containing ˜10 carbon atoms). Preferred heteroaryl groups include 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl. Also included within this term are groups in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic rings (eg, indolinyl, chromanyl, phenanthridinyl or tetrahydro-quinolinyl), Wherein the group or point of attachment is on the non-aromatic heteroatom-containing ring. Heteroaryl moieties include, but are not limited to, pyridine, pyrazine, thiazole, thiophene, oxadiazole, oxazole, pyrimidine, pyridazine, triazole, tetrazole, benzodioxole, benzofuran, benzodioxin, indole, benzimidazole, Benzofuran, indole, indazole, isoindole, benzothiophene, benzothiazole, benzoxazole, benzoisoxazole, benzoisothiazole, benzotriazole, furopyridine, furopyrimidine, furopyridazine, furopyrazine, furotriazine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine , Pyrrolopyrazine, pyrrolotriazine, thienopyridine, thienopyrimidine, thienopyridazine, thienopyra , Thienotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyridazine, thiazolopyrazine, thiazolotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine, oxazolopyrazine, oxazolotriazine, imidazopyridine, imidazopyrimidine , Imidazopyridazine, imidazopyrazine, imidazotriazine, pyrazolopyridine, pyrazolopyrimidine, pyrazolopyridazine, pyrazolopyrazine, pyrazolotriazine, triazolopyridine, triazolopyrimidine, triazolopyridazine, triazolopyrazine, quinoline, naphthyridine, Quinoxaline, quinazoline, isoquinoline, cinnoline, pyridopyridazine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, pteridine, pyrazi Pyridazine, pyrimido pyridazine, pyrimidopyrimidines include imidazothiazoles and thiazolo oxazole. All isomers of the above heteroaryl groups are within the scope of the invention. Each heteroaryl group may be attached at any ring carbon or, if the nitrogen is part of a 5-membered ring, attached through the nitrogen.

The term “heteroatom” means nitrogen, oxygen, or sulfur, and any oxidized form of nitrogen (eg, N (O) {N ⁺ —O ⁻ }) and sulfur (eg, S (O) and S (O)) ₂ ) as well as any quaternized type of basic nitrogen.

  The term “Het” refers to a 5 or 6 membered monocyclic heterocycle or an 8-11 membered bicyclic heterocycle system, any ring of which is either saturated, partially saturated or unsaturated, In the case of a single ring, it may be optionally benzo-fused or optionally spiro-fused, each Het being one or more carbon atoms and one boron atom and one or more oxygen atoms One boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms. Het may be attached at any carbon or N atom, provided that this attachment results in the creation of a stable structure. When Het has a substituent, it is understood that the substituent can be attached to any atom in the ring, but that results in a stable chemical structure. Preferred Het is oxaborolanyl, benzooxaborolyl, and dihydrobenzooxaborolyl.

  The term “heterocyclyl” refers to a 3-7 membered monocyclic heterocycle that is either saturated, partially saturated or unsaturated. Each heterocyclyl consists of one or more carbon atoms and one or more oxygen, nitrogen or sulfur atoms. The heterocyclyl may be attached at any carbon or N atom provided that this attachment results in the creation of a stable structure. If the heterocyclyl has a substituent, it is understood that the substituent can be attached to any atom in the ring, but that results in a stable chemical structure. A preferred heterocyclyl is imidazolyl.

  The invention features a compound of formula (I) as described above, wherein R is 1 or 2 halogens.

The invention features a compound of formula (I) as described above, wherein R ¹ is —C (O) NHR ⁵ .

The invention features a compound of formula (I) as described above, wherein R ² is C _3-6 cycloalkyl.

The invention features a compound of formula (I) as described above, wherein R ³ is —S (O) ₂ R ^7, wherein R ⁷ is C _1-6 alkyl.

In the present invention, R ⁴ is substituted with B (R ⁸ ) (R ⁹ ) (wherein R ⁸ and R ⁹ are both hydroxy), and further halogen, —CN, —C (H) F Features a compound of formula (I) above, which is C _6-10 aryl optionally substituted with one or more substituents independently selected from the group consisting of ₂ and —CF ₃ .

In the present invention, R ⁴ is substituted with B (R ⁸ ) (R ⁹ ) (wherein R ⁸ and R ⁹ are both hydroxy), and further halogen, —CN, —C (H) F ₂ And a compound of formula (I) above, which is a heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of —CF ₃ .

The invention features a compound of formula (I) as described above, wherein R ⁵ is C _1-6 alkyl.

The invention features a compound of formula (I) as described above, wherein R ⁶ is C _1-6 alkyl.

The invention features a compound of formula (I) as described above, wherein R ⁷ is C _1-6 alkyl.

  The invention features a compound of formula (I) as described above, wherein m is 1.

  The invention features a compound of formula (I) as described above, wherein X is alkylene.

The present invention relates to R being halogen; m is 1; R ¹ is —C (O) NHR ⁵ where R ⁵ is C _1-6 alkyl; R ² is C _3-6 Cycloalkyl; R ³ is —S (O) ₂ R ^7, where R ⁷ is C _1-6 alkyl, and R ⁴ is B (R ⁸ ) (R ⁹ ) or X ( R ⁸⁾ (R ⁹⁾ (wherein R ⁸ and R ⁹ is an C _6-10 aryl substituted with either a hydroxy); wherein C _6-10 aryl are halogen, -CN, - Features a compound of formula (I) that may be substituted with one or more substituents independently selected from the group consisting of C (H) F ₂ and —CF ₃ .

The present invention relates to R being halogen; m is 1; R ¹ is —C (O) NHR ⁵ where R ⁵ is C _1-6 alkyl; R ² is C _3-6 Cycloalkyl; R ³ is —S (O) ₂ R ^7, where R ⁷ is C _1-6 alkyl, and R ⁴ is B (R ⁸ ) (R ⁹ ) or X ( R ⁸ ) (R ⁹ ), where R ⁸ and R ⁹ are both hydroxy, where heteroaryl is halogen, —CN, —C (H) F ₂ And a compound of formula (I), optionally substituted with one or more substituents independently selected from the group consisting of —CF ₃ .

The present invention relates to R being halogen; m is 1; R ¹ is —C (O) NHR ⁵ where R ⁵ is C _1-6 alkyl; R ² is C _3-6 The group consisting of R ³ is —S (O) ₂ R ^7, where R ⁷ is C _1-6 alkyl, and R ⁴ is halogen, hydroxy, —CN, and oxo; Characterized by a compound of formula (I) which is Het substituted with one or more substituents independently selected from:

The present invention relates to R being halogen; m is 1; R ¹ is —C (O) NHR ⁵ where R ⁵ is C _1-6 alkyl; R ² is C _3-6 Cycloalkyl; R ³ is —S (O) ₂ R ^7, where R ⁷ is C _1-6 alkyl, and R ⁴ is independent of the group consisting of halogen, hydroxyl, and —CN. Characterized by a compound of formula (I) which is Het substituted with one or more substituents selected from

The present invention also provides a compound represented by formula (I) ′:

(Where:
R is F or Cl;
R ¹ is —C (O) NHR ⁵ ;
R ² is C _3-6 cycloalkyl;
R ³ is —S (O) ₂ R ⁷ ;
R ⁴ is
(a) Substituted with B (R ⁸ ) (R ⁹ ) or XB (R ⁸ ) (R ⁹ ), and further halogen, C _1-6 alkoxy, -C (H) F ₂ , -CF ₃ , C _{1- 6} alkyl, hydroxy, hydroxyalkyl, _{aminoalkyl, -C (O) NH 2,} -C (O) OH, -C (O) NHR 5, -S (O) 2 R 6, -S (O) 2 NH One or more substitutions independently selected from the group consisting of ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC (O) R ¹⁰ , C _3-6 cycloalkyl, and heterocyclyl Heteroaryl optionally substituted by a group;
(b) Substituted with B (R ⁸ ) (R ⁹ ) or XB (R ⁸ ) (R ⁹ ), and further halogen, C _1-6 alkoxy, -C (H) F ₂ , -CF ₃ , C _{1- 6} alkyl, hydroxy, hydroxyalkyl, _{aminoalkyl, -C (O) NH 2,} -C (O) OH, -C (O) NHR 5, -S (O) 2 R 6, -S (O) 2 NH One or more substituents independently selected from the group consisting of ₂ , -CN, -OCF ₃ , -OR ^6, -NR ¹⁰ R ¹¹ , -NHC (O) R ¹⁰ , C _3-6 cycloalkyl and heterocyclyl C _6-10 aryl optionally substituted by: or
(c) Halogen, C _1-6 alkoxy, -C (H) F ₂ , -CF ₃ , C _1-6 alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C (O) NH ₂ , -C (O) OH, -C (O) NHR ⁵ , -S (O) ₂ R ⁶ , -S (O) ₂ NH ₂ , -CN, -OCF ₃ , -OR ^6, -NR ¹⁰ R ¹¹ , -NHC (O) Het optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁰ , C _3-6 cycloalkyl, and heterocyclyl;
Het is a 5- or 6-membered monocyclic heterocycle or an 8- to 11-membered bicyclic heterocycle system, any ring of which is either saturated, partially saturated or unsaturated, and monocyclic Optionally benzo-fused, or optionally spiro-fused, where each Het is one or more carbon atoms and one boron atom and one or more oxygen atoms; Consisting of one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms,
R ⁵ is C _1-6 alkyl;
R ⁶ is C _1-6 alkyl or C _3-6 cycloalkyl;
R ⁷ is C _1-6 alkyl, hydroxyalkyl, or aminoalkyl;
R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5-14 membered ring, The ring includes carbon atoms and optionally one or more heteroatoms that may be N or O; the ring includes C _1-6 alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C (O) OH, C (O) OXOR ¹³ , C (O) N (R ¹⁰ ) (R ¹¹ ), N (R ¹⁰ ) (R ¹¹ ), and C _3-6 cycloalkyl (which are hydroxy, amino, halogen, C, respectively) Optionally substituted with one or more substituents independently selected from the group consisting of (O) OH, C (O) N (R ¹⁰ ) (R ¹¹ ), and N (R ¹⁰ ) (R ¹¹ ). Optionally substituted with one or more substituents independently selected from the group consisting of:
R ¹⁰ and R ¹¹ are each independently hydrogen or C _1-6 alkyl;
R ¹³ is alkoxy;
X is alkylene or —O-alkylene, where alkylene is halogen, C _1-6 alkoxy, —C (H) F ₂ , —CF ₃ , C _1-6 alkyl, hydroxy, hydroxyalkyl, aminoalkyl _{, -C (O) NH 2,} -C (O) OH, -C (O) NHR 5, -S (O) 2 R 6, -S (O) 2 NH 2, -CN, -OCF 3, - Optionally substituted with one or more substituents independently selected from the group consisting of OR ⁶ , —NR ¹⁰ R ¹¹ , —NHC (O) R ¹⁰ and C _3-6 cycloalkyl)
Or a pharmaceutically acceptable salt thereof.

In the present invention, R ⁴ is B (R ⁸ ) (R ⁹ ) or XB (R ⁸ ) (R ⁹ ), wherein R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl. Wherein the heteroaryl is one or more substituents independently selected from the group consisting of halogen, —CN, —C (H) F ₂ , and —CF _3. Features a compound of formula (I) ′ as described above, which may be substituted.

In the present invention, R ⁴ is B (R ⁸ ) (R ⁹ ) or XB (R ⁸ ) (R ⁹ ), wherein R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl. A C _6-10 aryl substituted with 1), wherein C _6-10 aryl is one independently selected from the group consisting of halogen, —CN, —C (H) F ₂ and —CF ₃ It is characterized by a compound of the above formula (I) ′ which may be substituted with the above substituents.

In the present invention, R ⁴ is halogen, C _1-6 alkoxy, —C (H) F ₂ , —CF ₃ , C _1-6 alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C (O) NH ₂ , -C (O) OH, -C (O) NHR ⁵ , -S (O) ₂ R ⁶ , -S (O) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -Het optionally substituted with one or more substituents independently selected from the group consisting of: -NHC (O) R ¹⁰ , C _3-6 cycloalkyl, and heterocyclyl; where Het is 5 or A 6-membered monocyclic heterocycle or an 8-11 membered bicyclic heterocycle system, where any ring is either saturated, partially saturated or unsaturated, where each Het is 1 One or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms Characterized by the compound of formula (I) ′ above.

In the present invention, R ⁴ is independently selected from the group consisting of halogen, C _1-6 alkoxy, —C (H) F ₂ , —CF ₃ , C _1-6 alkyl, hydroxy, hydroxyalkyl and aminoalkyl. Features a compound of formula (I) ′ above, which is Het optionally substituted with one or more substituents.

The invention features a compound of formula (I) ′ above, wherein R ⁶ is C _1-6 alkyl.

The invention features a compound of formula (I) ′ above, wherein R ⁷ is C _1-6 alkyl.

The invention features a compound of formula (I) ′ as described above, wherein R ⁸ and R ⁹ are each independently hydroxy.

  The invention features a compound of formula (I) ′ above, wherein X is alkylene.

The present invention relates to compounds of the formula (I) wherein R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5-8 membered ring; ) Or (I) ′. Such 5- to 8-membered rings include pinanediol, pinacol, perfluoropinacol, ethylene glycol, diethylene glycol, catechol, 1,2, -cyclohexanediol, 1,3-propanediol, 2,3, -butanediol, 1, Those formed from 2, -butanediol, 1,4-butanediol, glycerol and diethanolamine.

The present invention includes the following:
(2-chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid;
(2-chloro-4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid;
4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenylboronic acid;
3- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenylboronic acid;
4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenylboronic acid;
4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorophenylboronic acid;
4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenylboronic acid;
6- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) pyridin-3-ylboronic acid;
(4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (difluoromethyl) phenyl) boronic acid;
(4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (trifluoromethyl) phenyl) boronic acid;
(4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2,6-difluorophenyl) boronic acid;
(2-Cyano-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid
6- (N- (4-borono-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid;
(4- (N- (3-carbamoyl-2- (4-chlorophenyl) -5-cyclopropylbenzofuran-6-yl) methylsulfonamido) -2-chlorophenyl) boronic acid;
6- (N- (7-Chloro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamido) -5-cyclopropyl-2- (4-fluoro Phenyl) -N-methylbenzofuran-3-carboxamide;
(4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (methylsulfonyl) phenyl) boronic acid;
1- (2-chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) -4-methyl- 2,6,7-trioxa-1-borabicyclo [2.2.2] octane-1-wid;
((4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenoxy) methyl) boronic acid;
((2-chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenoxy) methyl) boronic acid;
5-cyclopropyl-2- (4-fluorophenyl) -6- (N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamide) -N -Methylbenzofuran-3-carboxamide;
(4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-cyanophenyl) boronic acid;
5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl) methylsulfonamido) benzofuran-3-carboxamide;
(2-chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenethyl) boronic acid;
5-Cyclopropyl-6- (N- (7-fluoro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamido) -2- (4-fluoro Phenyl) -N-methylbenzofuran-3-carboxamide;
6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-4-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N- Methylbenzofuran-3-carboxamide;
(3- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenethyl) boronic acid;
6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N- Methylbenzofuran-3-carboxamide;
6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N- Methylbenzofuran-3-carboxamide, enantiomer 1;
6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N- Methylbenzofuran-3-carboxamide, enantiomer 2;
5-Cyclopropyl-2- (4-fluorophenyl) -6- (N- (1-hydroxy-3,4-dihydro-1H-benzo [c] [1,2] oxaborin-6-yl) methylsulfonamide ) -N-methylbenzofuran-3-carboxamide;
And a pharmaceutically acceptable salt thereof selected from the group consisting of:

  Compounds of formula (I) and (I) ′ in which the boron-containing ring is directly linked to the sulfonamide are boron-containing compounds of PCT / US2011 / 024822 (WO2011 / 103063) and PCT / US2011 / 024824 (WO2012 / 067663) Shows enhanced metabolic stability compared to compounds in which the rings are linked via an alkylene linker. Comparative pharmacokinetic studies in rats, dogs, and monkeys showed that clearance was significantly improved (Table 2).

  Certain compounds of formula (I) and (I) ′ may exist in stereoisomeric forms (eg, they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention extends to conformational isomers of compounds of formula (I) and (I) ′, as well as any geometric (cis and / or trans) isomers of the compounds. Racemates may be separated using preparative HPLC and a column having a chiral stationary phase, or may be resolved to obtain individual enantiomers using methods known to those skilled in the art. Furthermore, chiral intermediate compounds can be resolved and used to prepare the chiral compounds of the present invention.

  Diastereoisomeric mixtures of the compounds of formula (I) and (I) ′ can be separated according to methods well known in the literature (eg preparative HPLC or chromatographic purification). Racemates may be separated using preparative HPLC and a column having a chiral stationary phase, or may be resolved to obtain individual enantiomers using methods known to those skilled in the art. Furthermore, chiral intermediate compounds can be resolved and used to prepare the chiral compounds of the present invention.

  It will be appreciated that compounds of formula (I) and (I) ′ may exist in tautomeric forms other than those shown in the formula and are within the scope of the present invention. .

  It will also be appreciated that compounds of the present invention present as polymorphs and mixtures thereof are within the scope of the present invention.

Substitution with an isotope (eg deuterium, ie ² H) may result in certain therapeutic benefits resulting from higher metabolic stability (eg, increased half-life or reduced required dose), so it depends on the situation Can do.

  The invention also features a compound of formula (I) or (I) ′ or a pharmaceutically acceptable salt thereof. The term “pharmaceutically acceptable” as used herein means a compound suitable for pharmaceutical use. The term “pharmaceutically acceptable”, when used in reference to an ingredient that can be included in a pharmaceutical composition for administration to a patient, is any other ingredient that is present in the pharmaceutical composition. Is acceptable in the sense of conforming to and not harmful to the recipient.

  Salts of the compounds of formula (I) and (I) ′ that are suitable for use in medicine are salts whose pharmaceutically acceptable ions. However, salts with pharmaceutically unacceptable counterions for use as intermediates in the preparation of other compounds of formula (I) or (I) ′ and their pharmaceutically acceptable salts, for example, are Is within the range. It will also be appreciated that for use in medicine the salts of formula (I) and (I) ′ must be physiologically (ie pharmaceutically) acceptable.

  The compounds of the present invention may be in the form of their free bases or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters thereof.

  The invention also encompasses pharmaceutically acceptable salt complexes. The present invention also covers pharmaceutically acceptable salts of the compounds of formula (I) and (I) ′. The term “pharmaceutically acceptable salt” as used herein refers to a salt that retains the desired biological activity of the subject compound and that exhibits minimal undesirable toxic effects. For a review of suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19. The term “pharmaceutically acceptable salts” includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or the purified form of the free acid form or the free base form, respectively, suitable. It may be prepared by reacting separately with a base or acid. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

  Thus, according to a further aspect, the present invention provides pharmaceutically acceptable salts of compounds of formula (I) or (I) ′ and embodiments thereof.

  In certain embodiments, the compound of formula (I) or (I) ′ may contain an acidic functional group, thus forming a pharmaceutically acceptable base addition salt by treatment with a suitable base. it can. A pharmaceutically acceptable base addition salt is obtained by reacting a compound of formula (I) or (I) ′ with a suitable strong base, optionally in a suitable solvent such as an organic solvent, to obtain a base addition salt. This base addition salt can be isolated, for example by crystallization and filtration. Pharmaceutically acceptable base salts include ammonium salts (e.g. ammonium salts or tetraalkylammonium salts), metal salts such as alkali metal or alkaline earth metal salts (e.g. hydroxide salts, sodium salts, potassium salts). Calcium salt or magnesium salt), organic amines (eg, tris [also known as tromethamine or tris (hydroxymethyl) aminomethane], ethanolamine, diethylamine, triethanolamine, choline, isopropylamine, dicyclohexylamine or N-methyl- D-glucamine), cationic amino acids (eg arginine, lysine or histidine) or insoluble salt bases (eg procaine or benzathine).

  In certain embodiments, the compound according to formula (I) or (I) ′ may contain a basic functional group, thus forming a pharmaceutically acceptable acid addition salt by treatment with a suitable acid. Can do. Pharmaceutically acceptable acid addition salts include compounds of formula (I) or (I) ′ and a suitable strong inorganic acid (such as hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or perchloric acid) or suitable Strong organic acids such as sulfonic acids [p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, naphthalenesulfonic acid (eg, 2-naphthalenesulfonic acid)], Carboxylic acids (e.g. acetic acid, propionic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid or succinic acid), anionic amino acids (e.g. glutamic acid or aspartic acid), hydroxy acids (e.g. citric acid, lactic acid, tartaric acid or glycolic acid) Fatty acids (e.g. caproic acid, caprylic acid, decanoic acid, oleic acid or stearic acid), or acids for insoluble salts (pamonic acid or resin) Fats (eg polystyrene sulfonate) etc.) can optionally be formed by reacting in a suitable solvent, such as an organic solvent, to obtain a salt, which is usually obtained by crystallization and filtration, for example. Isolated. In one embodiment, the pharmaceutically acceptable acid addition salt of the compound of formula (I) or (I) ′ is a strong acid salt such as hydrobromide, hydrochloride, hydroiodide, sulfate. Nitrate, perchlorate, phosphate, p-toluenesulfonate, benzenesulfonate or methanesulfonate.

  Those skilled in the art recognize that organic boronic acids and / or their organic boronic esters can form “ate” complex addition salts, such as organic borate complex addition salts, in the presence of suitable nucleophilic complexing reagents. I will be. Suitable nucleophilic complexing reagents include, but are not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or fluoride. Examples of organoborate complex addition salts and methods for their preparation will be readily appreciated. For example, one such suitable organic borate complex addition salt is a trihydroxy organic borate alkali metal salt such as trihydroxy organic borate sodium salt. By way of example, complex addition salts of sodium trihydroxyarylborate and sodium trihydroxyalkylborate and methods for their preparation are described in Cammidge, A.N. et al., Org. Lett., 2006, 8, 4071-4074. The pharmaceutically acceptable “ate” complex addition salts described herein are also considered to be within the scope of this invention.

  The present invention relates to acidic salts such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and tris (tromethamine-tris (hydroxymethyl) aminomethane) salts, or suitable acids such as Organic carboxylic acids such as acetic acid, lactic acid, tartaric acid, malic acid, isethionic acid, lactobionic acid and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and hydrochloric acid and sulfuric acid Characterized by suitable pharmaceutically acceptable salts of the compounds of formula (I) and (I) ′, including monobasic or dibasic salts with inorganic acids such as phosphoric acid and sulfamic acid.

  The present invention is a salt of a strong base such as sodium, lysine, ammonium, N-methyl-D-glucamine, potassium, choline, arginine (eg L-arginine) or magnesium, of formula (I) or (I) Characterized by a pharmaceutically acceptable base addition salt of the compound '. In a further embodiment, the salt is sodium, lysine, ammonium, N-methyl-D-glucamine, potassium, choline or arginine (eg, L-arginine).

  Other pharmaceutically unacceptable salts, such as oxalate salts, may be used, for example, in the isolation of compounds of formula (I) or (I) ′ and are within the scope of the present invention.

  The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I) and (I) ′.

  Salts of compounds of formula (I) and (I) ′ can be prepared by contacting a suitable stoichiometric amount of the free acid with a suitable base in a suitable solvent. The free acid of the compound of formula (I) or (I) ′ may be present in solution with the appropriate base added as a solid, or the free acid of the compound of formula (I) or (I) ′ And a suitable acid may be present independently in solution.

  Suitable solvents for solubilizing the free acid of the compound of formula (I) or (I) ′ include, for example, alcohols such as isopropanol; ketones such as acetone; acetonitrile or toluene. When the base is added as a solution in a solvent, the solvent used can include acetone, methanol or water.

  Salts of compounds of formula (I) or (I) ′ can be isolated in solid form from their solutions obtained as described above by conventional methods. For example, an amorphous salt is prepared by precipitation from solution, spray drying or freeze drying of the solution, vapor deposition of the solution on glass, or vacuum drying of the oil, or solidification of the metal resulting from the reaction of the free base with the acid. be able to.

  Salts of the compounds of formula (I) and (I) ′ can be obtained by crystallizing directly from the solvent in which the salt has limited solubility, or by crushing the amorphous salt or otherwise crystallizing it. Can be prepared. For example, organic solvents such as acetone, acetonitrile, butanone, 1-butanol, ethanol, 1-propanol or tetrahydrofuran, or a mixture of such solvents can be used. An improvement in the yield of the salt can be obtained by evaporating part or all of the solvent, or, for example, by stepwise crystallization at elevated temperature followed by controlled cooling. Careful control of the precipitation temperature and seeding can be used to improve the reproducibility of the manufacturing process and the particle size distribution and morphology of the product.

  One skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of the compounds of formula (I) and (I) ′ and solvates of the salts of the compounds of formula (I) and (I) ′ are included within the scope of the invention.

  The term “solvate” as used herein refers to a variable stoichiometry formed by a solute (in the present invention, a compound of formula (I) or (I) ′ or a salt thereof) and a solvent. Refers to a complex of theory. Such a solvent for the purposes of the present invention should not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Most preferably, the solvent used is water and the solvate may be referred to as a hydrate.

  Solvates of compounds of formula (I) and (I) ′ that are suitable for use in medicine are solvates in which the solvent is pharmaceutically acceptable. However, solvates with pharmaceutically unacceptable solvents for use as intermediates, for example in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and solvates are of the invention Is in range.

  Furthermore, some of the crystalline forms of compounds of formula (I) and (I) ′ or their salts and solvates may exist in one or more polymorphic forms, which are encompassed by the present invention. The

  Prodrugs of the compounds of formula (I) and (I) ′ are included within the scope of the invention.

  One skilled in the art will not be able to retain the pharmacological activity of a particular protected derivative of a compound of formula (I) or (I) ′ that can be made prior to the final deprotection step, although certain examples It will be appreciated that can be administered orally or parenterally and subsequently metabolized in the body to form a pharmacologically active compound as defined in the first embodiment. Accordingly, such derivatives can be represented as “prodrugs”. All protected derivatives and prodrugs of compounds defined in the first aspect are included within the scope of the invention. Examples of suitable prodrugs of the compounds of the present invention are described in Drugs of Today, Vol. 19, No. 9, 1983, pages 499-538 and Topics in Chemistry, Chapter 31, pages 306-316 and “Design by H. Bundgaard” of Prodrugs ”, Elsevier, 1985, Chapter 1 (the disclosure of this document is incorporated herein by reference). Prodrugs can also be made by methods disclosed in, for example, US 6,958,319 and US 6,297,217. Those skilled in the art are known to those skilled in the art as “pro moieties” as described, for example, by H. Bundgaard in “Design of Prodrugs”, the disclosure of which is incorporated herein by reference. It will further be appreciated that certain moieties may be located on such functional groups if appropriate functional groups are present in the compounds of formula (I) or (I) ′. Suitable prodrugs of the compounds of the present invention include esters, carbonates, hemiesters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals, ketals, Examples include boronic acid esters and boronic acid anhydrides.

  Boronic esters and anhydrides include boronic esters and anhydrides derived from sugars such as polysaccharides or disaccharides (eg, glucose, sucrose, fructose, xylitol, mannitol and sorbitol). Such boronic esters can be prepared by any method known to those skilled in the art, for example as described in the literature (“p-Boronophenylalanine Complexes with Fructose and Related Carbohydrates and Polyols” PCT / US00 / 07833). And “Cyclic Triolborates: Air- and Water-Stable Ate Complexes of Organoboronic Acids” Angew. Chem. International Edition 2008, 47, 928). Boronic esters and boronic anhydrides having a nitrogen atom bonded to boron can also be prepared as described in the literature by those skilled in the art (eg, “A Method for the Deprotection of Alkylpinacolyl Boronate Esters” J Org. Chem. 2011, 76, 3571 and also “Chemoselective Suzuki Coupling of Diborylmethane for Facile Synthesis of Benzylboronates” Org. Letters 2011, 13, 3368).

  The boronic acid is converted to the corresponding boronic ester in a suitable solvent (e.g. toluene) via treatment with an alcohol (e.g. ethanol) or diol (e.g. pinacol) with a dehydrating agent (e.g. powder molecular sieves). Can do.

  Since the compounds of the present invention have been found to exhibit antiviral activity (particularly HCV inhibitory activity), they can be useful in the treatment or prevention of viral infections such as HCV infection, or diseases associated with such infections.

  The present invention provides a compound of formula (I) or (I) ′ or a pharmaceutically acceptable salt thereof for use in drug therapy.

  The present invention relates to a compound of formula (I) or (I) ′ or a pharmaceutical thereof for the manufacture of a medicament for the treatment and / or prevention of viral infections such as HCV infection and / or diseases associated with such infections. Provide the use of acceptable salts.

  The present invention relates to a compound of formula (I) or (I) ′ or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of viral infections such as HCV infection and / or diseases associated with such infections I will provide a.

  The present invention provides a method for the treatment or prevention of a viral infection, such as an HCV infection, or a disease associated with such infection, comprising a therapeutically effective amount of a compound of formula (I) or (I) ′ or a pharmaceutically The above method is provided comprising administering an acceptable salt to a subject (eg, a human).

  It will be appreciated that references herein to “therapy” or “treatment” may include, but are not limited to, prevention, delay, prophylaxis and cure of the disease. Let's go. The present invention provides compounds and pharmaceutical compositions for the treatment of diseases associated with viral infections, such as HCV infection, and viral infections in living hosts. Furthermore, it will be appreciated that references herein to treatment or prevention of HCV infection include treatment or prevention of HCV related diseases such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

  The present invention provides compounds and pharmaceutical compositions for preventing viral infections, such as HCV infection, and diseases associated with viral infections in a living host. Furthermore, it will be appreciated that references herein to prevention or prevention of HCV infection include treatment or prevention of HCV related diseases such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

  Compounds of formula (I) and (I) ′ can be made by the processes described herein or any method known to one of ordinary skill in the art.

  The invention also encompasses a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable excipient. The term “excipient” refers to a compound (eg, diluent, carrier) useful in the preparation of a pharmaceutical composition.

  The compounds of the present invention can be administered in conventional dosage forms prepared by combining the compounds of the present invention and standard pharmaceutical carriers or diluents by conventional methods well known in the art. These methods may include mixing, granulating and compressing or dissolving the above ingredients as appropriate for the desired formulation. The above dosage forms and methods can be used for amorphous dispersions, molecular dispersions, hot melt extrusion, particle size reduction through micronization or wet bead milling (nano milling), self-emulsifying systems, or complex formation (eg cyclodextrin). ).

  The pharmaceutical composition of the present invention can be formulated for administration by any route, oral administration, topical administration, intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, transdermal administration or A pharmaceutical composition in a form suitable for transmucosal administration is included.

  For oral administration, the compound may be in any suitable dosage form such as tablets, capsules, powders, granules, troches, creams or solutions (eg, oral or sterile solutions or suspensions, syrups) Agents, elixirs and concentrated drop agents).

  Tablets and capsules for oral administration may be in unit dosage form, such as a binder (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone); a filler (eg lactose, sugar, corn starch, Conventional, such as tableting lubricants (eg, magnesium stearate, talc, polyethylene glycol or silica); disintegrants (eg, potato starch), or acceptable wetting agents (eg, sodium lauryl sulfate); Of excipients. The tablets may be coated according to methods well known in normal pharmaceutical practice. When the composition is in the form of a capsule, any routine encapsulation (eg hard gelatin capsule shell or soft gelatin capsule shell) is suitable. If the above composition is in the form of a soft gelatin capsule shell, consider any pharmaceutical carrier (eg, aqueous gum, cellulose, silicate or oil) routinely used to prepare dispersions or suspensions. These can be incorporated into soft gelatin capsule shells. Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or dry products for reconstitution with water or other suitable vehicle prior to use. May be presented as Such liquid formulations include suspending agents (eg, sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, ammonium stearate gel or hydrogenated edible oil); emulsifiers (eg, lecithin, sorbitan monooleate) Or acacia); non-aqueous vehicles (may include edible oils) (eg, almond oil, oily esters (such as glycerin, propylene glycol or ethyl alcohol)); preservatives (eg, methyl or propyl p-hydroxybenzoate, or sorbine) Conventional additives such as acid) and, optionally, conventional flavoring or coloring agents. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier (eg, ethanol, peanut oil, olive oil, glycerin or water) and a flavoring or coloring agent.

  For injection (parenteral administration) (eg, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration), a liquid unit preparation using the present compound and a sterile vehicle (eg, water, saline solution, Hank's solution or Ringer's solution) A shape is prepared. The compound may be suspended in or dissolved in the vehicle, depending on the vehicle and concentration used. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. In addition, the compounds of the invention may be formulated in solid form and redissolved or suspended immediately prior to use. A preparation in lyophilized form can also be produced. A typical parenteral composition is a solution of a compound or salt in a sterile aqueous or sterile non-aqueous carrier that may contain a parenterally acceptable oil (eg, polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil). Or a suspension.

  For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents can be used to promote penetration. Transmucosal administration can be accomplished through, for example, nasal sprays, rectal suppositories or vaginal suppositories. A typical suppository formulation comprises a compound of formula (I) or (I) ′, or a pharmaceutically acceptable salt thereof, which is active when administered in this manner, and a binder and / or lubricant (eg a polymer). Glycol, gelatin, cocoa butter or other low melting vegetable waxes or fats, or synthetic analogs thereof). Typical compositions for inhalation are in the form of solutions, suspensions or emulsions that can be administered as a dry powder, or conventional non-CFC propellants (eg, 1,1,1,2-tetrafluoroethane or 1,1 1,2,3,3,3-heptafluoropropane).

  The topical formulations of the present invention include, for example, ointments, creams, gels, salves or lotions, ophthalmic ointments and ophthalmic or otic drops, impregnated dressings and aerosols. Can be presented as an agent and may include suitable conventional additives (eg, preservatives), solvents to aid drug penetration, and emollients in ointments and creams. The formulation may also include compatible conventional carriers for lotions, such as cream or ointment bases and ethanol or oleyl alcohol.

  The preparation may be suitably formulated to give controlled / extended release of the active compound.

The amount of various compounds to be administered depends on the (IC ₅₀ ) titer, (EC ₅₀ ) potency of the compound, and the biological half-life (of the compound), the patient's age, size and weight, and the patient's It can be determined by standard methods, taking into account factors such as the disease or disorder to be. The importance of these and other factors to consider is known to those of ordinary skill in the art.

  The amount administered will also depend on the route of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, a relatively high dose would have to be administered. Oral administration is the preferred method of administration of the compound.

  Preferably, the composition is in unit dosage form. For oral application, for example, tablets or capsules can be administered; for nasal application, a metered aerosol dose may be administered; for transdermal application, a topical or patch formulation is administered It is possible, and for transmucosal delivery, buccal patches can be administered. In either case, the dosage is such that the patient can be administered a single dose.

  In general, suitable dosages for each of the above conditions are in the range of 0.01 to 250 mg per kilogram of body weight of the recipient (e.g., human) per day and in the range of 0.1 to 100 mg per kilogram of body weight per day It will be in the range of 0.5-30 mg per kilogram of body weight per day and in the range of 1.0-20 mg per kilogram of body weight per day. Unless indicated otherwise, the total weight of active ingredient is calculated as the parent compound of formula (I) or (I) ′; for their salts or esters, the weight will increase proportionally. The desired dose can be given as 1, 2, 3, 4, 5, 6 or more sub-doses administered at appropriate intervals throughout the day. In some cases, the desired dose may be given every other day or other suitable schedule (eg, once a week or once a month). These sub-doses can be administered, for example, in unit dosage forms containing 0.5 to 100 mg, 5 to 1000 mg or 50 to 500 mg, or 20 to 500 mg, or 50 to 400 mg of active ingredient per unit dosage form.

  One of ordinary skill in the art will determine the optimal amount and interval of administration of individual doses of the compounds of the invention, depending on the nature and severity of the condition being treated, the dosage form, route and site, and the particular mammal being treated, It will also be appreciated that such optimum conditions can be determined by conventional techniques. Also, those skilled in the art can determine the optimal course of treatment (ie, the number of administrations of the compound of the present invention given per day for a specified number of days) by using the conventional course of therapeutic decision testing. You will understand that too.

  The compound of formula (I) or (I) ′ or a pharmaceutically acceptable salt thereof can also be used in combination with other therapeutic agents. Accordingly, the present invention provides, in a further aspect, a combination comprising a compound of formula (I) or (I) ′ or a pharmaceutically acceptable salt thereof together with one or more additional therapeutic agents.

  The compounds of the present invention may contain other therapeutic agents such as immunotherapeutic agents (eg interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents (corticosteroids or NSAIDs), bronchodilators (eg β-2 adrenergic agonists). Drugs and xanthines (eg theophylline)), mucolytic agents, antimuscarinic agents, anti-leukotriene agents, cell adhesion inhibitors (eg ICAM antagonists), antioxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surface It can be administered in combination with active agents and / or antibacterial and antiviral agents (eg, ribavirin and amantidine). The composition according to the invention can also be used in combination with gene replacement therapy.

  The compounds of the present invention can be administered in combination with other therapeutic antiviral agents selected from the following list: interferon, pegylated interferon, ribavirin, protease inhibitors (eg telapravir, boceprevir, BMS650032 , GS9256, BI201335, IDX320 or compounds disclosed in PCT / US2010 / 046782); polymerase inhibitors (eg, firibvir, VX222, GS7977, GS9190, PSI938, PSI7792, BI207127, R7128, IDX184); NS5a (eg, Daclatasvir) and NS4a Or other viral proteins inhibitors such as NS4b, small interfering RNA compounds, antisense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antiviral agents, and Anti-infective compound. For example, combination therapy may include a compound of formula (I) or (I) ′ or a pharmaceutically acceptable salt thereof and other antiviral agents (eg, acyclovir, famciclovir, valganciclovir and related compounds, ribavirin and related compounds) , Amantadine and related compounds), various interferons (eg, interferon-α, interferon-β, interferon-γ, etc.) and alternative forms of interferon (eg, pegylated interferon).

  Interferons include interferon-α, pegylated interferon-α, a combination of interferon-α and ribavirin, and a combination of interferon-α and levovirin. Interferon-α includes, but is not limited to, recombinant interferon-α2a, interferon-α2b, consensus interferon, and purified interferon-α product.

  The compositions and methods of the invention feature a compound of formula (I) or (I) ′ and interferon. The interferon can be selected from the group consisting of interferon-α2b, pegylated interferon-α, consensus interferon, interferon-α2a, and lymphoblastoid interferon τ.

  The compositions and methods of the present invention include compounds of formula (I) or (I) ′ and interleukin 2, interleukin 6, interleukin 12, RNA, antisense RNA, imiquimod, ribavirin, inosine 5′-monophosphate Characterized by a compound having anti-HCV activity selected from the group consisting of a dehydrogenase inhibitor, amantadine and rimantadine.

  When a compound of formula (I) or (I) ′ or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent, the dose of each compound is different from the dose when the compound is used alone. obtain. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in therapy will depend on the nature of the condition being treated and the age and condition of the patient and ultimately at the discretion of the attending physician or attending veterinarian.

  The above mentioned combinations can be conveniently presented for use in the form of a pharmaceutical composition, so that the combination defined above comprises at least one pharmaceutically acceptable carrier and Pharmaceutical compositions comprising with / or excipients constitute another aspect of the present invention.

  The individual components of such combinations can be administered sequentially or simultaneously as separate or combined pharmaceutical compositions by any convenient route.

  If administration is continuous, either the HCV inhibitor or the second therapeutic agent may be administered first. When administration is simultaneous, the above combinations may be administered as the same pharmaceutical composition or as different pharmaceutical compositions.

  It will be appreciated that when combined in the same formulation, the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, any convenient formulation can be conveniently provided in a manner as known for such compounds in the art.

  The following non-limiting examples illustrate the invention.

  One skilled in the art will appreciate that when a solvent is used in the reaction, it is desirable to use an anhydrous solvent. Where appropriate, it is further desirable to carry out the reaction under an inert atmosphere, for example under nitrogen or argon.

Compounds of formula (I) and (I ′) can be prepared by the following methods or any method known to those skilled in the art.

A compound of formula (I) of type IX (R _a = halogen, R _b and R _c = halogen, alkyl, alkoxy, or ring) corresponds to the corresponding bromide (III) compound or the corresponding triflate (IV, where P = OTf) is readily prepared from compounds using conditions known to those skilled in the art. For example, conversion to the corresponding pinacol boronate III a solvent (e.g., 1,4-dioxane) catalyst with heating (e.g. 80 ° C.) in a (e.g. PdCl ₂ (dppf)), a base (e.g. KOAc), boron It can be achieved by treatment with a source (eg bis-pinacol diboron). Subsequent treatment with an acid (eg, HCl) with a pinacol scavenger (eg, polymer-supported benzeneboronic acid) or sodium periodate in a solvent mixture (eg, THF / water) to give IX. Furthermore, one skilled in the art will be able to convert nitro II to the corresponding aniline using reducing conditions involving a catalyst (e.g., 10% palladium on carbon) in a solvent (e.g., THF) under a hydrogen atmosphere. You will recognize. Thereafter, III is obtained using a Sandmeyer reaction involving an oxidizing agent (eg, sodium nitrite), an acid (eg, HBr) and cuprous bromide in a solvent (eg, MeCN). Triflate (IV, where P = OTf) compounds can be produced by treating the corresponding phenol intermediate IV (where P = H) with a triflating reagent (eg, triflic anhydride).

Compounds II, III and IV are prepared from the corresponding sulfonamide V (where R _a = halogen), nitro-fluoroarene (VI) or bromoboronic acid (VII) or phenol-protected boronic acid (VIII, where P = benzyl ) Can be easily obtained. In the former case, V is treated directly with a base (eg LiHMDS or potassium carbonate) in a solvent (eg DMF) and then exposed to VI to give the corresponding SN _AR substitution product II. In addition, sulfonamides can be obtained using Chan-Lam coupling conditions that include a copper source (e.g., copper (II) acetate), a base (e.g., triethylamine), and a desiccant (e.g., 3 or 4Å molecular sieves) in a solvent (e.g., DCM). Treatment of V with an aryl boronic acid such as VII or VIII (where P = benzyl) gives the corresponding bromide III or phenol protected intermediate IV (where P = benzyl), which is deprotected (e.g. benzyl (By hydrogenation of the group) affords phenol intermediate IV (wherein P = H).

Bicyclic oxaboryl analogs such as X can be made in a similar manner. For example, by coupling the corresponding sulfonamide V (where Ra = halogen) and nitro-fluoroarene VI in a solvent (e.g. DMF) in the presence of a base (e.g. LiHMDS or potassium carbonate), such as XI A compound is obtained. Nitro XI can be converted to the corresponding aniline XII (where X = H) using reducing conditions that include a catalyst (eg, 10% palladium on carbon) in a solvent (eg, THF) under a hydrogen atmosphere. The corresponding aniline XII is obtained by a person skilled in the art via a Sandmeyer reaction in which aniline XII is treated with an oxidizing agent (e.g. sodium nitrite), acid (e.g. HBr) and cuprous bromide in a solvent (e.g. MeCN). To bromide XIII (X = H). Alternatively, aniline XII (where X = H) is treated with an electrophilic halogen source (e.g., N-chlorosuccinimide) in a solvent (e.g., MeCN) to give the corresponding halogenated aniline XII (where X = Cl) can be obtained. This aniline can then be converted to the corresponding bromide XIII (where X = Cl) by the Sandmeyer reaction described above. Ester functionality of intermediate XIII (wherein X = H or Cl), the solvent (e.g., THF) number of different reducing agents in (e.g., LiBH ₄₎ corresponding benzylic alcohol XIV (wherein the P = It can be reduced to H). Protection of alcohols with any number of protecting groups (e.g. -MOM) can be achieved by those skilled in the art with benzylic alcohol XIV (where P = H) in a solvent (e.g. THF) with a base (e.g. DIPEA) and protection. It can be achieved by treatment with a group (eg MOM-Cl) to give the MOM protected benzylic alcohol XIV (where P = MOM). The above bromide can then be converted to the corresponding boronate ester by one of ordinary skill in the art. For example, XIV conversion to the corresponding pinacol boronate (P = MOM wherein) a solvent (e.g., 1,4-dioxane) in the heating (e.g., 80 ° C.) while a catalyst (e.g. PdCl ₂ (dppf)) Can be achieved by treatment with a base (eg KOAc), a boron source (eg bis-pinacol diboron). Subsequent treatment with an acid (eg HCl) in a solvent (eg THF) removes both the pinacol ester and the MOM protecting group, thereby forming the bicyclic oxaboryl analog X.

In a manner similar to that described above, a compound of type XV can be obtained directly by treating a compound of formula V with a compound of XVI in a solvent (eg, THF) in the presence of a base (eg, sodium hydride or LHMDS). Can be obtained. Conversion of the resulting bromide to a compound of formula XVI can be accomplished in an analogous manner to the conversion of compound III to compound IX.

Boronic acid type XVII a base (e.g., K ₂ CO ₃₎ and in the presence a suitable solvent (e.g., DMF) in the corresponding phenol intermediate IV a (wherein P = H) 2-(chloromethyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane). Removal of the pinacol group under the conditions described herein provides the corresponding boronic acid XVII. One skilled in the art will recognize that type XVIII benzylic acid boronic acids can be obtained from the corresponding type IX boronic acid esters or from the corresponding type III bromides. For example, as described in the literature (e.g., J. Med. Chem. 2010, 53, 7852), in a suitable solvent (e.g., THF), at low temperature (e.g., -78 ° C) Treatment of the protected pinacol boronic ester IX with LiCH ₂ Cl gives the corresponding benzylic boronic ester XVIII (where R _d = H). Alternatively, the corresponding benzylic boronic ester of type XVIII (wherein R _d = H) is a suitable alkyl lithium (e.g., -78 ° C) in a suitable solvent (e.g., THF) at a low temperature (e.g., -78 ° C). , TBuLi), followed by halogen-metal exchange followed by 2- (chloromethyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane) It can be prepared from type III aryl bromides. Alternatively, the corresponding type XVIII benzylic boronic ester is appropriately substituted with an aryl bromide as described in the literature (e.g. J. Am. Chem. Soc. 2010, 132, 11033). It can be prepared from an appropriately substituted type III aryl bromide by Pd-catalyzed cross coupling with a bis-boronic acid ester such as XIX where R _d = alkyl, benzyl.

Type XX cyclic oxaboryl (wherein R _e = H, alkyl) can be prepared by a multi-step route as described in the literature. For example, as described in the literature (J. Org. Chem. 2011, 76, 3997 or Chem. Commun. 2009, 5987), metal catalysts (e.g., CuCl or Rh (Phebox) XXIII) In the presence of bis-pinacol borane (B ₂ pin ₂ ) type XXII α, β-unsaturated ester (e.g., R _f = OMe), amide (e.g., R _f = NMe ₂ ), and Reaction with a ketone (e.g., R _f = alkyl) yields an intermediate of type XXI where reduction of the ester, amide, or ketone and removal of pinacol is performed to give the corresponding cyclic oxaboryl XX (formula R _e = H, alkyl).

  The regioisomeric cyclic oxaboryls XXIV and XXV are readily prepared by hydroborating the corresponding alkenes (XXVI and XXVII, respectively) according to standard conditions described in the literature.

Intermediate Synthesis Intermediate 1: 2- (4-Chlorophenyl) -5-cyclopropyl-N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide

Step 1: Ethyl 3- (4-chlorophenyl) -3-oxopropanoate
To a solution of 4-chlorobenzoic acid (30.0 g, 0.192 mol) in DCM (250 mL) was added oxalyl chloride (25 mL, 0.288 mol) followed by dropwise addition of DMF (0.5 mL). The reaction mixture was refluxed for 2 hours. The resulting clear yellow solution was concentrated in vacuo to give the acid chloride as a yellow liquid. TEA (67 mL) was added to a solution of potassium ethyl malonate (41 g, 0.241 mol) in acetonitrile (537 mL). Cooled in an ice-salt bath, MgCl ₂ (27.4 g, 0.288 mol) was added and the resulting mixture was stirred at this temperature for 3 hours. Acid chloride (prepared as described above) was added and the reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was cooled in an ice bath and 2N HCl (600 mL) was carefully added. The mixture was stirred in an ice bath for 1.5 hours, then transferred to a separatory funnel and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated sodium bicarbonate (450 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product ethyl 3- (4-chlorophenyl)- 3-Oxopropanoate (48.6 g) was obtained and used without purification.

Step 2: Ethyl 2- (4-chlorophenyl) -5-hydroxybenzofuran-3-carboxylate Zinc chloride (28.3 g, 0.207 mol) is stirred in absolute ethanol (45 mL) and then with oven dried glassware The mixture was heated to 95 ° C. (reflux) under a nitrogen atmosphere. Ethyl 4-chlorobenzoyl acetate (44 g, 0.194 mol) was added in one portion and then a solution of benzoquinone (22.6 g, 0.21 mol) in anhydrous MTBE (500 mL) was added dropwise over 2 hours. This reaction was performed by simultaneously distilling MTBE from the reaction mixture so that the reaction volume was maintained at approximately quantitative. Throughout the addition, a bath temperature of 145-155 ° C and an internal temperature of 75-95 ° C were maintained. Additional ethanol (45 mL) was added during the addition as the reaction mixture became highly viscous and there was some concern that the original volume of ethanol would be reduced during the distillation. Heating was continued for 30 minutes after the addition was complete. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solid was removed by filtering the biphasic solution, then the organic layer was separated, washed with additional water, dried and evaporated in vacuo. The remaining brown solid was slurried in warm dichloromethane and the mixture was further cooled by cooling to room temperature and freezing overnight. The tan solid was filtered from the dark brown solution, washed with a small amount of DCM and dried under vacuum to give ethyl 2- (4-chlorophenyl) -5-hydroxybenzofuran-3-carboxylate (27 g, 44%). Obtained.

Step 3: Ethyl 2- (4-chlorophenyl) -5-isopropoxybenzofuran-3-carboxylate
To ethyl 2- (4-chlorophenyl) -5-hydroxybenzofuran-3-carboxylate (26 g, 0.051 mol) in NMP (160 mL) was added isopropyl bromide (15 mL), followed by cesium carbonate (33 g, 0.101 mol). added. The reaction mixture was stirred in a 60 ° C. oil bath for 20 hours and then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 minutes. The mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 2- (4-chlorophenyl) -5-isopropoxybenzofuran-3-carboxylate (15 g, 82%) Got.

Step 4: Ethyl 2- (4-chlorophenyl) -5-isopropoxy-6-nitrobenzofuran-3-carboxylate Ethyl 2- (4-chlorophenyl) -5-isopropoxybenzofuran-3-carboxylate 4 (30 g, 0.084 mol) was dissolved in chloroform (75 mL) and the resulting solution was cooled in an ice bath. Nitric acid (55 mL) was also dissolved in chloroform (75 mL) and cooled in an ice bath. The acidic solution was added dropwise over 1 hour to a solution of ethyl 2- (4-chlorophenyl) -5-isopropoxybenzofuran-3-carboxylate and then the reaction mixture was stirred at 0 ° C. for 1.5 hours. The reaction mixture was then diluted with water (60 mL) and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil which was purified by column chromatography (5 / 1PE / EA) to give ethyl 2- (4-chlorophenyl). ) -5-isopropoxy-6-nitrobenzofuran-3-carboxylate was obtained as a brown solid (11 g, 32%).

Step 5: Ethyl 2- (4-chlorophenyl) -5-hydroxy-6-nitrobenzofuran-3-carboxylate Ethyl 2- (4-chlorophenyl) -5-isopropoxy-6-nitrobenzofuran-3-carboxylate (11 g 27.2 mmol) was dissolved in anhydrous DCM (150 mL) and cooled in an ice bath under a nitrogen atmosphere. Boron trichloride (41 mL, 41.0 mmol) was added over about 20 minutes. After the reaction was complete, the reaction mixture was quenched by pouring into an ice / water mixture. The mixture was extracted with DCM and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give ethyl 2- (4-chlorophenyl) -5-hydroxy-6-nitrobenzofuran-3-carboxy. The rate was obtained (10.2 g, 84%).

Step 6: Ethyl-2- (4-chlorophenyl) -6-nitro-5- (trifluoromethylsulfonyloxy) benzofuran-3-carboxylate ethyl 2- (4-chlorophenyl) -5-hydroxy-6-nitrobenzofuran- A solution of 3-carboxylate (10.2 g, 22.9 mmol) and DMAP (0.289 g, 2.3 mmol) in anhydrous DCM (300 mL) and anhydrous TEA (4.8 mL) in trifluoromethanesulfonic anhydride under nitrogen in an ice bath (5.62 mL, 34 mmol) was added. The reaction mixture was stirred at 0 ° C. for 30 min under nitrogen, then quenched with water (200 mL) at 0 ° C. and extracted with DCM (3 × 200 mL). The combined organic layers were washed with water (3 × 600 mL), 2N HCl (2 × 300 mL), water (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, ethyl 2- (4-Chlorophenyl) -6-nitro-5- (trifluoromethylsulfonyloxy) benzofuran-3-carboxylate (10 g, 80%) was obtained as a yellow solid, which was used without further purification.

Step 7: Ethyl 2- (4-chlorophenyl) -5-cyclopropyl-6-nitrobenzofuran-3-carboxylate
2- (4-Chlorophenyl) -6-nitro-5- (trifluoromethylsulfonyloxy) benzofuran-3-carboxylate (10 g, 18 mmol), KF (4.64 g, 79.9 mmol), NaBr (2.48 g, 24 mmol), To a mixture of cyclopropylboronic acid (3.2 g, 37 mmol) and Pd (Ph ₃ P) ₄ (1.33 g, 1.15 mmol), toluene (130 mL) and water (2.8 mL) were added. The reaction flask was evacuated for about 3 minutes and then filled with nitrogen. The reaction mixture was refluxed for 20 hours under nitrogen and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (150 mL), washed with water (3 × 200 mL), brine (200 mL), dried over anhydrous sodium sulfate, decanted and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1-10 / 1) to give ethyl 2- (4-chlorophenyl) -5-cyclopropyl-6-nitrobenzofuran-3-carboxylate. Obtained as a yellow solid (7.9 g, 99%).

Step 8: Ethyl 6-amino-2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylate Ethyl 2- (4-chlorophenyl) -5-cyclopropyl-6-nitrobenzofuran-3-carboxylate ( To a solution of 8 g, 18.2 mmol) in ethyl acetate (450 mL) was added 10% palladium on carbonate (1.83 g), 1 N HCl solution (2.5 mL) and stirred at 0.4 MPa hydrogen at room temperature for 8 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give ethyl 6-amino-2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylate as a brown solid (7.4 g 99%).

Step 9: Ethyl 2- (4-chlorophenyl) -5-cyclopropyl-6- (N- (methylsulfonylmethyl) methylsulfonamido) benzofuran-3-carboxylate ethyl 6-amino-2- (4-chlorophenyl)- To a solution of 5-cyclopropylbenzofuran-3-carboxylate (7.4 g, 18.06 mmol) in dry dichloromethane (170 mL) was added dry TEA (6.73 mL, 45.15 mmol) at −15 ° C. under N ₂ atmosphere, then methane. Sulfonyl chloride (4.91 mL, 63.2 mmol) was added dropwise. The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 × 150 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give ethyl 2- (4-chlorophenyl) -5-cyclopropyl-6- (N- (methylsulfonylmethyl) methylsulfonamide. ) Benzofuran-3-carboxylate was obtained (9.2 g, 99%).

Step 10: 5-Cyclopropyl-2- (4-chlorophenyl) -6- (methylsulfonamido) benzofuran-3-carboxylic acid potassium hydroxide (15.1 g, 270 mmol) in ethyl 2- (4- Chlorophenyl) -5-cyclopropyl-6- (N- (methylsulfonylmethyl) methylsulfonamido) benzofuran-3-carboxylate was added to a solution in ethanol (64 mL) and water (32 mL). The reaction was refluxed for 1 hour and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1N HCl (250 mL) until a precipitate formed. The solid was filtered then dried to give 5-cyclopropyl-2- (4-chlorophenyl) -6- (methylsulfonamido) benzofuran-3-carboxylic acid (8.7 g, quantitative yield).

Step 11: 2- (4-Chlorophenyl) -5-cyclopropyl-N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide
To a solution of 5-cyclopropyl-2- (4-chlorophenyl) -6- (methylsulfonamido) benzofuran-3-carboxylic acid (5 g, 11.52 mmol) in dry DMF (30 mL) at 20 ° C., DIPEA (3.3 g, 25.34 mmol) and HATU (5.15 g, 13.5 mmol) were added. After 15 minutes, 2M methylamine in THF (23.04 mL, 46.08 mmol) was added dropwise and the mixture was stirred for an additional 2 hours before adding water (60 mL). The mixture was extracted with EA (3 × 200 mL), washed with water (2 × 200 mL), dried and concentrated to 2- (4-chlorophenyl) -5-cyclopropyl-N-methyl-6- (Methylsulfonamido) benzofuran-3-carboxamide was obtained as a brown solid (4.7 g, 97%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.32 (br. S., 1 H) 8.45 (q, 1 H) 7.90 (d, 2 H) 7.53-7.64 (m, 3 H) 7.16 (s , 1 H) 3.06 (s, 3 H) 2.83 (d, 3 H) 2.21-2.37 (m, 1 H) 0.94-1.05 (m, 2 H) 0.64-0.73 (m, 2 H). LCMS (m / z, ES ⁺ ) = 419 (M + H +).

Intermediate 2: 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide

Step 1: Methyl 2- (4-fluorophenyl) -5-hydroxy-1-benzofuran-3-carboxylate Anhydrous zinc chloride (25 g, 183 mmol) in anhydrous methanol using an oven-dried glassware under a nitrogen atmosphere (60 mL) and then the internal temperature was heated to 75 ° C. Methyl 4-fluorobenzoyl acetate (39.6 g, 202 mmol) was added in one portion and then a solution of p-benzoquinone (19.83 g, 183 mmol) in anhydrous diethyl ether (500 mL) was added dropwise over 4 hours. This was done by simultaneously distilling ether from the reaction mixture so that the reaction volume was kept almost constant (if the bath temperature was 140 ° C, the internal temperature was initially 75 ° C and then gradually increased). Maintained at a maximum of 115 ° C). 2.5 hours after the start of benzoquinone addition, methanol (20 mL) was further added to facilitate stirring. After the benzoquinone addition was complete, heating of the reaction mixture was continued at 100 ° C. (internal) for 1 hour. The reaction mixture was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate (800 mL). Insoluble solids were removed from the biphasic solution by filtration, then the organic layer was separated, dried (Na ₂ SO ₄ ), filtered and evaporated under vacuum. The brown residue was slurried in warm dichloromethane (ca. 225 mL) and the mixture was placed in the refrigerator for 18 hours. The resulting solid is filtered from the dark brown solution, washed with a small amount of dichloromethane and then dried under vacuum to give methyl 2- (4-fluorophenyl) -5-hydroxy-1-benzofuran-3-carboxylate. Obtained. LCMS (m / z, ES ⁺ ) = 285 (M-1).

Step 2: Methyl 2- (4-fluorophenyl) -5-[(1-methylethyl) oxy] -1-benzofuran-3-carboxylate Methyl 2- (4-fluorophenyl) -5-hydroxy-1-benzofuran A mixture of -3-carboxylate (18.86 g, 65.9 mmol), isopropyl bromide (24.74 mL, 264 mmol) and cesium carbonate (42.9 g, 132 mmol) in dry N-methyl-2-pyrrolidone (191 mL) was added under nitrogen. Stir at 20 ° C. for 20 hours. The resulting thick suspension was cooled to room temperature and then 7% aqueous ammonia (200 mL) was added with rapid stirring. This mixture was extracted with heptane (700 mL) and then the aqueous phase was separated. Ethyl acetate (ca. 100 mL) was added to the organic phase and the resulting mixture was shaken and then dried over Na ₂ SO ₄ and evaporated to give a brown oil that crystallized overnight. This material is recrystallized from hot methanol, the solid is filtered off, washed with methanol and finally dried under vacuum to give methyl 2- (4-fluorophenyl) -5-[(1-methylethyl) oxy ] -1-Benzofuran-3-carboxylate was obtained. LCMS (m / z, ES ⁺ ) = 329 (M + 1). The mother liquor from the first recrystallization was crystallized a second time to give a further batch of methyl 2- (4-fluorophenyl) -5-[(1-methylethyl) oxy] -1-benzofuran-3-carboxylate. It was.

Step 3: Methyl 2- (4-fluorophenyl) -5-[(1-methylethyl) oxy] -6-nitro-1-benzofuran-3-carboxylate methyl 2- (4-fluorophenyl) -5- [ (1-Methylethyl) oxy] -1-benzofuran-3-carboxylate (6.16 g, 18.76 mmol) in chloroform (22 mL) at −15 ° C. with 70% nitric acid (11 mL, 172 mmol) in chloroform (22 mL) Medium cooling solution was added dropwise. After stirring for 1 hour at 0 ° C., the reaction mixture was washed with water (50 mL) and the organic phase was separated by a hydrophobic filter tube and then evaporated under vacuum to give a brown solid. The solid was triturated in methyl tert-butyl ether (25 mL) and the resulting pale yellow powder was filtered off, washed with heptane, dried under vacuum and methyl 2- (4-fluorophenyl) -5- [ (1-Methylethyl) oxy] -6-nitro-1-benzofuran-3-carboxylate was obtained. ^{LCMS (m / z, ES +} ) = 764 (2M + NH 4) +.

Step 4: Methyl 2- (4-fluorophenyl) -5-hydroxy-6-nitro-1-benzofuran-3-carboxylate methyl 2- (4-fluorophenyl) -5-[(1-methylethyl) oxy] To a stirred solution of -6-nitro-1-benzofuran-3-carboxylate (5.237 g, 14.03 mmol) in dry dichloromethane (70 mL), a 1M solution of boron trichloride in dichloromethane (23.85 mL under a nitrogen atmosphere at -15 ° C). 23.85 mmol) was added over 30 minutes using a syringe pump. The dark reddish brown reaction mixture was poured onto ice (ca. 250 mL). The ice was thawed and the mixture was extracted with dichloromethane (ca. 450 mL). The organic phase was separated by a hydrophobic filter tube and evaporated under vacuum to give methyl 2- (4-fluorophenyl) -5-hydroxy-6-nitro-1-benzofuran-3-carboxylate. ¹ H NMR (d ₆ -DMSO): δ 10.97 (1H, br.s), 8.34 (1H, s), 8.07 (2H, dd), 7.67 (1H, s), 7.43 (2H, t), 3.86 ( 3H, s).

Step 5: Methyl 2- (4-fluorophenyl) -6-nitro-5-{[(trifluoromethyl) sulfonyl] oxy} -1-benzofuran-3-carboxylate Ice-cold methyl 2- (4-fluorophenyl) ) -5-hydroxy-6-nitro-1-benzofuran-3-carboxylate (4.915 g, 14.84 mmol) and 4- (dimethylamino) pyridine (0.181 g, 1.484 mmol) in anhydrous dichloromethane (130 mL) Under nitrogen, triethylamine (3.10 mL, 22.26 mmol) was added followed by trifluoromethanesulfonic anhydride (3.76 mL, 22.26 mmol). After 50 minutes at 0 ° C., water was added and the organic layer was separated. The aqueous phase was further extracted with dichloromethane and the combined organics were washed with 2M HCl and water. The organics were dried through a hydrophobic filter tube and evaporated to methyl 2- (4-fluorophenyl) -6-nitro-5-{[(trifluoromethyl) sulfonyl] oxy} -1-benzofuran-3-carboxylate Got. ^{LCMS (m / z, ES +} ) = 481 (M + NH 4) +.

Step 6: Methyl 5-cyclopropyl-2- (4-fluorophenyl) -6-nitro-1-benzofuran-3-carboxylate methyl 2- (4-fluorophenyl) -6-nitro-5-{[(tri Fluoromethyl) sulfonyl] oxy} -1-benzofuran-3-carboxylate (7.12 g, 15.37 mmol), cyclopropylboronic acid (2.19 g, 25.5 mmol), potassium fluoride (3.26 g, 56.1 mmol), sodium bromide (1.75 g, 17.01 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.85 g, 0.736 mmol) were stirred together in a mixture of toluene (90 mL) and water (2.25 mL) under nitrogen at 100 ° C. For 18 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic phase was separated, dried with a hydrophobic filter tube and evaporated under vacuum. The residue was purified by flash chromatography eluting on silica gel with a gradient of 0-5% ethyl acetate in cyclohexane. The product containing fractions were evaporated under vacuum to give methyl 5-cyclopropyl-2- (4-fluorophenyl) -6-nitro-1-benzofuran-3-carboxylate. ^{LCMS (m / z, ES +} ) = 728 (2M + NH 4) +.

Step 7: Methyl 6-amino-5-cyclopropyl-2- (4-fluorophenyl) -1-benzofuran-3-carboxylate
A solution of methyl 5-cyclopropyl-2- (4-fluorophenyl) -6-nitro-1-benzofuran-3-carboxylate (3.175 g, 8.94 mmol) in ethyl acetate (250 mL) containing 2M HCl (17 drops). Was stirred with 10% palladium on carbon (0.951 g, 0.894 mmol) under a hydrogen atmosphere at 21 ° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give a dark green solid. This is dissolved in dichloromethane, washed with sodium bicarbonate solution, separated by hydrophobic frit, then evaporated to dryness and purified by flash chromatography eluting on silica gel with a gradient of 0-30% ethyl acetate in cyclohexane. did. Appropriate fractions were combined and evaporated under vacuum to give methyl 6-amino-5-cyclopropyl-2- (4-fluorophenyl) -1-benzofuran-3-carboxylate. LCMS (m / z, ES ⁺ ) = 326 (M + H ⁺ ).

Step 8: Methyl 6- [bis (methylsulfonyl) amino] -5-cyclopropyl-2- (4-fluorophenyl) -1-benzofuran-3-carboxylate methyl 6-amino-5-cyclopropyl-2- ( A solution of 4-fluorophenyl) -1-benzofuran-3-carboxylate (1.96 g, 6.02 mmol) and triethylamine (2.52 mL, 18.07 mmol) in dry dichloromethane (40 mL) was cooled to 0 ° C. (ice bath), It was then treated with methanesulfonyl chloride (1.174 mL, 15.06 mmol). The reaction was stirred at 0 ° C. (ice bath) for 2 hours. Water (100 mL) is added and the organics are extracted three times with dichloromethane, dried using a hydrophobic frit, evaporated to dryness and methyl 6- [bis (methylsulfonyl) amino] -5-cyclopropyl-2- (4-Fluorophenyl) -1-benzofuran-3-carboxylate was obtained. LCMS (m / z, ES ⁺ ) = 482 (M + H ⁺ ).

Step 9: 5-cyclopropyl-2- (4-fluorophenyl) -6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxylic acid methyl 6- [bis (methylsulfonyl) amino] -5-cyclo A suspension of propyl-2- (4-fluorophenyl) -1-benzofuran-3-carboxylate (2.88 g, 5.98 mmol) in ethanol (50 mL) and water (25 mL) was added to potassium hydroxide (6.71 g, 120 mmol). ) And heated to reflux for 1 hour (when heated, the suspension turned into a solution). The reaction was concentrated in vacuo, water (100 mL) was added and the solution was acidified with 2M HCl (50 mL). The resulting precipitate was filtered, washed with 0.5M HCl and then dissolved in methanol. The solution was evaporated to dryness and azeotroped twice with toluene to give 5-cyclopropyl-2- (4-fluorophenyl) -6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxylic acid. Obtained. LCMS (m / z, ES ⁺ ) = 390 (M + H ⁺ ).

Step 10: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxylic acid (2.52 g, 6.47 mmol), HATU (2.95 g, 7.77 mmol) and triethylamine A solution of (1.984 mL, 14.24 mmol) in dry dichloromethane (100 mL) was stirred at room temperature for 1 hour and then treated with methylamine (16.18 mL, 32.4 mmol). The solution was stirred at room temperature for 4 hours under nitrogen, during which time a precipitate formed. The reaction was diluted with dichloromethane (300 mL) and sodium bicarbonate solution (200 mL) and stirred for 10 minutes. The layers were separated and the aqueous layer was further extracted with dichloromethane (150 mL). The combined organics were washed with brine (200 mL), dried using a hydrophobic frit and evaporated to dryness to give an off-white solid. The crude product was purified by flash chromatography (eluting with 0-100% ethyl acetate / cyclohexane followed by 10% methanol / dichloromethane) to give a white solid. The solid is dissolved in heated methanol-chloroform (10 vol / vol%), pre-adsorbed on silica gel and purified by flash chromatography (0-10% methanol / dichloromethane) to give 5-cyclopropyl-2- (4 -Fluorophenyl) -N-methyl-6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxamide was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.30 (br s, 1 H) 8.42 (q, 1 H) 7.88-7.98 (m, 2 H) 7.60 (s, 1 H) 7.37 (t, 2 H) 7.16 (s, 1 H) 3.06 (s, 3 H) 2.83 (d, 3 H) 2.23-2.36 (m, 1 H) 0.93-1.05 (m, 2 H) 0.65-0.74 (m, 2 H) . LCMS (m / z, ES ⁺ ) = 403 (M + H +).

Example 1: (2-Chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid

Step 1: 6- (N- (3-Chloro-4-nitrophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (12.5 g, 31.1 mmol), 2-chloro-4-fluoronitrobenzene (10.9 g, A mixture of 62.1 mmol) and potassium carbonate (12.9 g, 93.0 mmol) in 4: 1 DME / water (130 mL) was heated to 100 ° C. with stirring in a sealed flask. The same 12.5 g scale reaction was performed in a second sealed vessel. The reaction vessel was maintained at 100 ° C. for 70 hours, cooled to room temperature and stirred for an additional 18 hours. The combined reaction mixture was partitioned between EtOAc (300 mL) and water (600 mL) and the phases separated. The aqueous solution was extracted twice more with EtOAc (150 mL). The combined EtOAc solution was washed with half saturated brine (1 ×), saturated brine (1 ×), dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting tan solid was recrystallized from EtOAc / ether to give the title compound (22.3 g, 64%) as an off-white solid. LCMS (m / z, ES ⁺ ) = 558 (M + H ⁺ ).

Step 2: 6- (N- (4-Amino-3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (3-Chloro-4-nitrophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (11.0 g, 19.7 mmol) A solution in 1: 1 THF / MeOH (75 mL) was subjected to hydrogenation at 40 psi in the presence of 5% platinum sulfide on carbon (0.560 g). After 4 hours, additional catalyst was added (0.250 g). After an additional 16 hours, the reaction vessel was purged with nitrogen and the catalyst was removed by filtration through celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from hexane / EtOAc to give the title compound (10.3 g, 99%) as a white solid. LCMS (m / z, ES ⁺ ) = 528 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide equipped with mechanical stirrer In a 1 L three-necked flask, 6- (N- (4-amino-3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide ( 10.0 g, 18.9 mmol) followed by acetonitrile (200 mL) followed by 48% aqueous HBr (200 mL). The resulting highly viscous and agglomerated suspension was vigorously stirred for 30 minutes to obtain a more uniform suspension. The reaction vessel was cooled in an ice-water bath for 30 minutes and the mixture was treated with a solution of sodium nitrite (1.96 g, 28.4 mmol) in water (20 mL) with an addition funnel over 5 minutes. The resulting yellow suspension was stirred in an ice bath for 1.5 hours and then treated with CuBr (4.1 g, 28.4 mmol) in portions over 5 minutes. This gave a dark brown solution which was warmed to 60 ° C. (internal temperature) with continued stirring. After 40 minutes at elevated temperature, the mixture was cooled to room temperature and poured into a rapidly stirred mixture of 5% aqueous sodium bisulfite (600 mL) and EtOAc (800 mL). The phases were separated and the aqueous solution was extracted twice more with EtOAc (150 mL). The combined EtOAc solution was washed with 5% aqueous sodium bisulfite (2 x 150 mL), saturated aqueous sodium bicarbonate (2 x 300 mL), saturated brine (1 x 200 mL), dried over sodium sulfate and reduced in vacuo. Concentration to dryness gave a yellow foam. This material was subjected to flash chromatography (silica gel, 9: 1 hexane / EtOAc to EtOAc gradient). A white solid crystallized out while concentrating the pure fractions. After concentration to a thick suspension, the mixture was diluted with hexane (150 mL) and the mixture was stirred at room temperature overnight. The solid was filtered off in a medium fritted funnel and dried in vacuo to give the title compound (8.55 g, 76%) as a white crystalline solid. LCMS (m / z, ES ⁺ ) = 591, 593 (M + H ⁺ ).

Step 4: (2-Chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid Magnetic stirring To a 350 mL screw cap flask equipped with a vessel, add 6- (N- (4-bromo-3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3- Carboxamide (8.54 g, 14.4 mmol), bis (pinacolato) diboron (18.3 g, 72.1 mmol), potassium acetate (7.08 g, 72.1 mmol), Pd (II) (dppf) Cl ₂ dichloromethane complex (0.589 g, 0.721 mmol) And anhydrous 1,4-dioxane (150 mL) was added. The mixture was sparged with nitrogen for 10 minutes. The vessel was sealed and heated in an 80 ° C. oil bath with stirring. After 4 hours, the mixture was cooled to room temperature and diluted with EtOAc (400 mL). The resulting black solution was washed with water (2 times), saturated brine (1 time) and dried over sodium sulfate. While stirring with sodium sulfate, celite was added to facilitate removal of the insoluble black material that remained suspended in the solution. The mixture was filtered through a medium frit to give a golden brown filtrate, which was concentrated to dryness under reduced pressure. The residue was dissolved in THF (300 mL) and the resulting solution was cooled in an ice-water bath. The solution was treated with 1N aqueous HCl (120 mL) followed by sodium periodate (46.3 g, 216 mmol). The mixture was stirred at 0 ° C. for 10 minutes and then warmed to room temperature. After 18 hours, the mixture was partitioned between water and EtOAc and the phases were separated. The aqueous solution was extracted with EtOAc (twice). The combined EtOAc solution was washed with 5% aqueous sodium bisulfite (4 times), saturated brine (2 times), dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was flash chromatographed (silica gel, 2 partial gradients: DCM to EtOAc over 15 minutes, then solvent switched from A = 9: 1 DCM / MeOH, B = DCM; 100% B to 65% A over 4 minutes Followed by a gradient of 65% A for 15 minutes) to give a light tan foam (7.28 g). This material was dissolved in acetonitrile (75 mL) and 0.25N aqueous HCl (175 mL) was added rapidly dropwise over 20 minutes while stirring the solution. A white suspension formed and was stirred at room temperature. After 2 hours, the solid was filtered off in a medium fritted funnel. The filter cake was washed with water (twice), suction dried for 30 minutes and then dried in vacuo overnight to give the title compound (5.90 g, 74%) as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.90-7.97 (m, 2 H) 7.85 (s, 1 H) 7.29-7.41 (m, 4 H) 7.26 (t, 2 H) 3.34 (s, 3 H) 2.95 (s, 3 H) 2.07-2.17 (m, 1 H) 0.69-1.08 (m, 3 H) 0.49 (br s, 1 H). LCMS (m / z, ES ⁺ ) = 557 (M + H +).

Example 2: (2-Chloro-4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid

Step 1: 6- (N- (3-Chloro-4-nitrophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
2- (4-Chlorophenyl) -5-cyclopropyl-N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (2.00 g, 4.77 mmol), 2-chloro-4-fluoronitrobenzene (1.68 g, 9.55 mmol), and potassium carbonate (1.98 g, 14.3 mmol) in 4: 1 DME / water (20 mL) were heated to 100 ° C. with stirring in a sealed vessel. After 18 hours, the mixture was further treated with potassium carbonate (2.00 g), heated at 100 ° C. for an additional 15 hours, and then stirred at room temperature for 3 days. The mixture was partitioned between EtOAc and water. After phase separation, the aqueous portion was extracted twice more with EtOAc. The combined EtOAc solution was washed with water (2 times), brine (1 time), dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude was subjected to flash chromatography (silica gel, DCM to 7: 3 DCM / EtOAc gradient) to give a sticky yellow foam. This material was crystallized from hexane / EtOAc to give the title compound (1.78 g, 65%) as a pale yellow solid. LCMS (m / z, ES ⁺ ) = 574 (M + H ⁺ ).

Step 2: 6- (N- (4-Amino-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
6- (N- (3-chloro-4-nitrophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.500 g, 0.870 mmol) A solution in 1 MeOH / THF (30 mL) was subjected to hydrogenation at 45 psi in the presence of 5% platinum sulfide on carbon (50 mg). After 18 hours, the reaction vessel was purged with nitrogen, the catalyst was removed by filtration through celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from hexane / EtOAc to give the title compound (0.45 g, 95%) as an off-white solid. LCMS (m / z, ES ⁺ ) = 544 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
6- (N- (4-amino-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.421 g, 0.773 mmol) in 25 mL acetonitrile The medium stirred suspension was treated with 48% aqueous HBr (25 mL) and the resulting suspension was cooled in an ice-water bath. To the mixture was added a solution of sodium nitrite (0.056 g, 0.812 mmol) in water (2 mL). After stirring at 0 ° C. for 30 minutes, more sodium nitrite (14 mg) in water (1 mL) was added. After stirring for an additional 30 minutes at 0 ° C., the mixture was treated with CuBr (0.130 g, 0.906 mmol) in 4 portions over 5 minutes. The mixture was warmed to 60 ° C. for 30 minutes and then cooled to room temperature. The mixture was partitioned between EtOAc and 5% aqueous sodium bisulfite. The EtOAc solution was washed with 5% aqueous sodium bisulfite solution (2 times), saturated aqueous sodium bicarbonate solution (2 times), brine (1 time), dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient from hexane to 3: 7 hexane / EtOAc) followed by recrystallization from hexane / EtOAc to give the title compound (0.212 g, 45%) as a white solid. Obtained. LCMS (m / z, ES ⁺ ) = 609 (M + H ⁺ ).

Step 4: (2-Chloro-4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid
6- (N- (4-Bromo-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.205 g, 0.337 mmol), bis ( Pinacolato) diboron (0.428 g, 1.69 mmol), potassium acetate (0.165 g, 1.69 mmol) and Pd (II) (dppf) Cl _{2 in} dichloromethane complex (0.0138 g, 0.017 mmol) in anhydrous 1,4-dioxane (4 mL) The mixture was sparged with nitrogen for 10 minutes in a sealed tube. The vessel was sealed and heated with stirring in an 80 ° C. oil bath. After 4 hours, the mixture was cooled to room temperature and diluted with EtOAc. The resulting solution was washed with water (2 times), saturated brine (1 time) and dried over sodium sulfate. While stirring with sodium sulfate, celite was added to facilitate removal of the insoluble black material that remained suspended in the solution. The mixture was filtered through a medium frit to give a golden brown filtrate which was concentrated to dryness under reduced pressure. The residue was dissolved in THF (10 mL) and the resulting solution was cooled in an ice-water bath. The solution was treated with 1N aqueous HCl (4 mL) followed by sodium periodate (1.08 g, 5.05 mmol). The mixture was stirred at 0 ° C. for 10 minutes and then warmed to room temperature. After 18 hours, the mixture was partitioned between water and EtOAc and the phases were separated. The aqueous solution was extracted with EtOAc (2 times). The combined EtOAc solution was washed with 5% aqueous sodium bisulfite (4 times), saturated brine (2 times), dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was flash chromatographed (silica gel, 2 partial gradient: DCM to EtOAc over 15 minutes, then solvent switched from A = 9: 1 DCM / MeOH, B = DCM; 100% B to 65% over 4 minutes A gradient to A followed by 65% A isocratic 15 minutes) gave a light tan foam (0.142 g). This material was dissolved in acetonitrile (3 mL) and 0.25 N aqueous HCl (10 mL) was added dropwise over 20 minutes while stirring the solution. A white suspension formed and was stirred at room temperature. After 2 hours, the solid was filtered off in a medium fritted funnel. The filter cake was washed with water (2 times), air dried for 30 minutes, then dried in vacuo overnight to give the title compound (0.119 g, 62%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 8.50 (q, 1 H) 8.32 (s, 2 H) 8.11 (s, 1 H) 7.92 (d, 2 H) 7.62 (d, 2 H) 7.30- 7.45 (m, 3 H) 7.19 (s, 1 H) 3.40 (s, 3 H) 2.83 (d, 3 H) 2.06-2.16 (m, 1 H) 0.72-1.07 (m, 3 H) 0.52 (br s , 1 H). LCMS (m / z, ES ⁺ ) = 573 (M + H +).

Example 3: 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenylboronic acid

Step 1: 6- (N- (4-Bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxamide (500 mg, 1.244 mmol), 4-bromophenylboronic acid (1.5 g, 7.464 mmol), copper (II) acetate monohydrate (372 mg, 1.866 mmol), triethylamine (252 mg, 2.488 mmol), and 4Å molecular sieves (1 g) in dichloromethane (160 mL) were stirred for 2 days. . The solution was filtered, concentrated to dryness and purified by column chromatography to give 6- (N- (4-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N- Methylbenzofuran-3-carboxamide (180 mg, 0.323 mmol, 26% yield) was obtained as a brown solid. LCMS (m / z, ES ⁺ ) = 557, 559 (M + H ⁺ ).

Step 2: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) phenyl) methylsulfonamido) benzofuran-3-carboxamide
6- (N- (4-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (150 mg, 0.269 mmol), potassium acetate (80 mg, 0.807 mmol), bis (pinacolato) diboron (205 mg, 0.807 mmol), and Pd (dppf) Cl ₂ dichloromethane complex (22 mg, 0.027 mmol) in 1,4-dioxane (20 mL) with stirring. Maintained overnight at ° C. The solution was cooled to room temperature, filtered, concentrated to dryness and purified by column chromatography to give 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (4- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) benzofuran-3-carboxamide (152 mg, 0.251 mmol, 94% yield) was obtained as a brown solid It was. LCMS (m / z, ES ⁺ ) = 605 (M + H ⁺ ).

Step 3: 4- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenylboronic acid
5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Suspension of phenyl) methylsulfonamido) benzofuran-3-carboxamide (152 mg, 0.251 mmol), polymer-supported benzeneboronic acid (480 mg, 1.255 mmol), and 5N aqueous HCl (0.35 mL, 1.757 mmol) in tetrahydrofuran (15 mL) Was stirred at room temperature for 48 hours. The solution was filtered, concentrated to dryness and purified by reverse phase HPLC to give 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl). Methylsulfonamido) phenylboronic acid (45 mg, 0.086 mmol, 34% yield) was obtained as a white solid. ¹ H NMR (methanol-d ₄ ) δ: 7.98 (d, 1H), 7.96 (d, 1H), 7.87 (S, 1H), 7.66 (d, 2H), 7.46 (d, 2H), 7.32-7.26 ( m, 3H), 3.33 (s, 3H), 2.99 (s, 3H), 2.22-2.18 (m, 1H), 1.10-0.37 (m, 4H). LCMS (m / z, ES ⁺ ) = 523 (M + H +)

Example 4: 3- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenylboronic acid

Step 1: 6- (N- (3-Bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxamide (500 mg, 1.24 mmol), 3-bromophenylboronic acid (1.5 g, 7.46 mmol), copper (II) acetate monohydrate (372 mg, 1.87 mmol), triethylamine (252 mg, 2.49 mmol), 4Å molecular sieves (1 g) in dichloromethane (160 mL) was stirred for 2 days. The solid was filtered off and the filtrate was concentrated to dryness and purified by column chromatography to give 6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (270 mg, 0.48 mmol, 39% yield) was obtained as a brown solid. LCMS (m / z, ES ⁺ ) = 557, 559 (M + H ⁺ ).

Step 2: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) phenyl) methylsulfonamido) benzofuran-3-carboxamide
6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (240 mg, 0.43 mmol), potassium acetate (128 mg, 1.29 mmol), bis (pinacolato) diboron (328 mg, 1.29 mmol), and Pd (dppf) Cl ₂ dichloromethane complex (35 mg, 0.043 mmol) in 1,4-dioxane (20 mL) were stirred overnight. While maintaining at 95 ° C. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was concentrated to dryness and purified by column chromatography to give 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) benzofuran-3-carboxamide (269 mg, 0.45 mmol, 92% yield) was obtained as a brown solid. LCMS (m / z, ES ⁺ ) = 605 (M + H ⁺ ).

Step 3: 3- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenylboronic acid
5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) A suspension of (phenyl) methylsulfonamido) benzofuran-3-carboxamide (269 mg, 0.45 mmol), polymer-supported benzeneboronic acid (770 mg, 2.23 mmol), 5N aqueous HCl (0.62 mL, 3.12 mmol) in tetrahydrofuran (15 mL). And stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated to dryness and purified by reverse phase HPLC to give 3- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6- Yl) methylsulfonamido) phenylboronic acid (41 mg, 0.078 mmol, 17% yield) was obtained as a white solid. ¹ H NMR (methanol-d ₄ ) δ 7.99-7.95 (m, 2H), 7.94 (s, 1H), 7.77-7.38 (m, 4H), 7.32-7.25 (m, 3H), 3.32 (s, 3H) , 2.98 (s, 3H), 2.29-2.25 (m, 1H), 1.10-0.37 (m, 4H). LCMS (m / z, ES ⁺ ) = 523 (M + H +).

Example 5: 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenylboronic acid

Step 1: 5-cyclopropyl-6- (N- (3-fluoro-4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
2,4-Difluoro-1-nitrobenzene (261 mg, 1.64 mmol) and 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6-[(methylsulfonyl) amino] -1-benzofuran-3- A suspension of carboxamide (600 mg, 1.49 mmol) in dimethoxyethane (0.8 mL) and water (0.2 mL) was treated with potassium carbonate (616.86 mg, 4.47 mmol) and heated to 100 ° C. for 24 hours. The reaction mixture was concentrated and purified by column chromatography to give 5-cyclopropyl-6- (N- (3-fluoro-4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N- Methylbenzofuran-3-carboxamide (230 mg, 0.43 mmol, 29% yield) was obtained as a yellow powder. LCMS (m / z, ES ⁺ ) = 542 (M + H ⁺ ).

Step 2: 6- (N- (4-Amino-3-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-Cyclopropyl-6- (N- (3-fluoro-4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (230 mg, 0.43 mmol) and chloride A mixture of stannous (291 mg, 1.29 mmol) in ethyl acetate (5 mL) and ethanol (5 mL) was maintained at reflux for 3 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness and purified by column chromatography to give 6- (N- (4-amino-3-fluorophenyl) methylsulfonamido) -5-cyclopropyl- 2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide (200 mg, 0.39 mmol, 90% yield) was obtained as a yellow powder. LCMS (m / z, ES ⁺ ) = 512 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-3-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-amino-3-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (200 mg, 0.39 mmol) in acetonitrile A suspension in (5 mL) and aqueous hydrogen bromide (5 mL) was treated with aqueous sodium nitrite (29.6 mg, 0.43 mmol) with stirring at 0 ° C. for 0.5 h. Then cuprous bromide (64.3 mg, 0.45 mmol) was added in portions to the solution at 0 ° C. and heated to reflux for 2 hours. The solution was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated to dryness and purified by column chromatography to give 6- (N- (4-bromo-3-fluorophenyl) methylsulfonamide) -5- Cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (140 mg, 0.24 mmol, 61% yield) was obtained as a white solid. LCMS (m / z, ES ⁺ ) = 575, 577 (M + H ⁺ ).

Step 4: 5-cyclopropyl-6- (N- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamide) -2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (140 mg, 0.24 mmol) and bis A suspension of (pinacolato) diboron (914 mg, 3.60 mmol) in anhydrous dioxane (5 mL) was treated with PdCl ₂ (dppf) (19.6 mg, 0.024 mmol), potassium acetate (47.04 mg, 0.48 mmol) and N ₂ Under stirring, the temperature was maintained at 90 ° C. for 4 hours. The suspension was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated to dryness and purified by column chromatography to give 5-cyclopropyl-6- (N- (3-fluoro-4- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (140 mg, 0.22 mmol, yield) Yield 56%) as a white solid. LCMS (m / z, ES ⁺ ) = 623 (M + H ⁺ ).

Step 5: 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenylboronic acid
5-cyclopropyl-6- (N- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamide) -2- A solution of (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (140 mg, 0.22 mmol) and 1N aqueous HCl (2 mL) in anhydrous THF (10 mL) was treated with polymer-supported benzeneboronic acid (5000 mg), Stir at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated to dryness and purified by reverse phase HPLC to give 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (Methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenylboronic acid (50 mg, 0.092 mmol, 42% yield) was obtained as a white solid. ¹ H NMR (300 MHz, methanol-d4) δ 7.96 (dd, 2H), 7.83 (s, 1H), 7.45-7.15 (m, 6H), 3.43 (s, 3H), 2.96 (s, 3H), 2.12 (m, 1H), 1.01-0.52 (m, 4H). LCMS (m / z, ES +) = 541 (M + H +)

Example 6: 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorophenylboronic acid

Step 1: 5-Cyclopropyl-6- (N- (2-fluoro-4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxamide (402 mg, 1 mmol), 1,2-difluoro-4-nitrobenzene A mixture of (318 mg, 2 mmol) and potassium carbonate (414 mg, 3 mmol) in 1,2-dimethoxyethane (20 mL) and water (5 mL) was heated at 100 ° C. for 48 h. The solution was cooled to room temperature, concentrated, diluted with ethyl acetate (50 mL) and washed with water. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness and purified by column chromatography to give 5-cyclopropyl-6- (N- (2-fluoro-4-nitrophenyl) methylsulfonamide)- 2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide (420 mg, 0.77 mmol, 77% yield) was obtained as a yellow solid. LCMS (m / z, ES ⁺ ) = 542 (M + H ⁺ )

Step 2: 6- (N- (4-Amino-2-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-Cyclopropyl-6- (N- (2-fluoro-4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (420 mg, 0.77 mmol) and chloride A suspension of tin (II) dihydrate (519 mg, 2.31 mmol) in ethyl acetate (15 mL) and ethanol (15 mL) was heated at 80 ° C. for 2 hours. The solution was cooled to room temperature, concentrated, diluted with ethyl acetate (50 mL) and washed with sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness and purified by column chromatography to give 6- (N- (4-amino-2-fluorophenyl) methylsulfonamido) -5-cyclopropyl- 2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide (360 mg, 0.7 mmol, 91% yield) was obtained as a yellow solid. LCMS (m / z, ES ⁺ ) = 512 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-2-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-amino-2-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (360 mg, 0.7 mmol) in acetonitrile To a solution in (20 mL) was added hydrobromic acid (5 mL, 40% in water) at 0 ° C. followed by sodium nitrite (49 mg, 0.77 mmol in 2 mL water). After stirring at 0 ° C. for 10 minutes, cuprous bromide (115 mg, 0.8 mmol) was added. The mixture was warmed to 80 ° C. and stirred for 1 hour. The mixture was cooled to room temperature and diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL), dried over sodium sulfate, filtered, concentrated to dryness and purified by column chromatography to give 6- (N- (4-bromo-2-fluoro Phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (240 mg, 0.42 mmol, 60% yield) was obtained as an off-white solid. LCMS (m / z, ES ⁺ ) = 575, 577 (M + H ⁺ ).

Step 4: 5-cyclopropyl-6- (N- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamide) -2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-2-fluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (240 mg, 0.42 mmol), acetic acid Suspension of potassium (123 mg, 1.26 mmol), bis (pinacolato) diboron (533 mg, 2.1 mmol) and PdCl ₂ (dppf) (68.5 mg, 0.084 mmol) in 1,4-dioxane (30 mL) under nitrogen Heated at 100 ° C. with stirring for 16 hours. The solution was cooled to room temperature, filtered, concentrated and purified by column chromatography to give 5-cyclopropyl-6- (N- (2-fluoro-4- (4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl) phenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (200 mg, 0.32 mmol, 76% yield) pale yellow Obtained as a solid. LCMS (m / z, ES ⁺ ) = 623 (M + H ⁺ ).

Step 5: 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorophenylboronic acid
5-Cyclopropyl-6- (N- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamide) -2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide (200 mg, 0.32 mmol), polymer-supported benzeneboronic acid (600 mg, 1.60 mmol) and 5N aqueous HCl (0.45 mL, 2.24 mmol) in tetrahydrofuran (20 mL) The suspension was stirred at room temperature for 24 hours. The solution was filtered, concentrated to dryness and purified by reverse phase HPLC to give 4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl). Methylsulfonamido) -3-fluorophenylboronic acid (61 mg, 0.11 mmol, 35% yield) was obtained as a white solid. ¹ H NMR (methanol-d ₄ ) δ 8.03 (s, 1H), 7.97-7.79 (m, 2H), 7.57 (dd, 3H), 7.24 (dd, 3H), 3.29 (s, 3H), 2.94 (s , 3H), 2.42 (s, 1H), 1.00 (d, 2H), 0.69 (s, 2H). LCMS (m / z, ES ⁺ ) = 541 (M + H +).

Example 7: 4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenylboronic acid

Step 1: 6- (N- (4- (Benzyloxy) -3-fluorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
2- (4-Chlorophenyl) -5-cyclopropyl-N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (2.0 g, 4.77 mmol), (4- (benzyloxy) -3-fluorophenyl) A mixture of boronic acid (1.762 g, 7.16 mmol), Cu (OAc) ₂ (1.301 g, 7.16 mmol), triethylamine (3.33 mL, 23.87 mmol) and powdered 3Å molecular sieves (2 g) in CH ₂ Cl ₂ (60 mL). Was stirred in a flask equipped with a drying tube open to the air. After 12 hours, the mixture was further treated with (4- (benzyloxy) -3-fluorophenyl) boronic acid (1.762 g, 7.16 mmol) and Cu (OAc) ₂ (1.301 g, 7.16 mmol) for 4 days at room temperature. Stir. The mixture was diluted with CH ₂ Cl ₂ and filtered through celite and the dark brown filtrate was concentrated to dryness. The crude was purified by flash chromatography on silica gel (0-4% EtOAc / CH ₂ Cl ₂ ) to give the desired compound which was further eluted on silica gel eluting with (0-40% EtOAc / hexanes). Was purified by flash chromatography to give the desired compound as a light tan solid (406 mg, 14%). LCMS (m / z, ES ⁺ ) = 619 (M + H ⁺ ).

Step 2: 2- (4-Chlorophenyl) -5-cyclopropyl-6- (N- (3-fluoro-4-hydroxyphenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide
6- (N- (4- (benzyloxy) -3-fluorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide (350 mg, 0.565 mmol) Was dissolved in ethyl acetate (8.0 mL) and ethanol (8.0 mL). 10% Pd / C (30.1 mg, 0.283 mmol) was added followed by H ₂ (1 atm, balloon). The mixture was stirred at room temperature for 2 hours and filtered through celite. The filtrate was concentrated to dryness and rinsed twice with hexanes to give the desired product as a white solid, which was used without further purification. LCMS (m / z, ES ⁺ ) = 529 (M + H ⁺ ).

Step 3: 4- (N- (2- (4-Chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenyl trifluoromethanesulfonate
Tf ₂ O (0.157 mL, 0.930 mmol) in CH ₂ Cl ₂ (1 mL) was added 2- (4-chlorophenyl) -5-cyclopropyl-6- (N- (3-fluoro) at room temperature under N _2. -4-hydroxyphenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide (328 mg, 0.620 mmol) and pyridine (0.251 mL, 3.10 mmol) were added dropwise to a suspension in CH ₂ Cl ₂ (5 mL). . The mixture was stirred at room temperature for 3 hours and then water was added. The mixture was extracted with CH ₂ Cl _2, the combined organic phases were dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure flash chromatography on silica gel eluting with (0 to 40% EtOAc / hexanes) To give the desired compound as a white solid (410 mg, 83% yield). LCMS (m / z, ES ⁺ ) = 661 (M + H ⁺ ).

Step 4: 2- (4-Chlorophenyl) -5-cyclopropyl-6- (N- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide
4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenyltrifluoromethanesulfonate (170 mg, 0.257 mmol), 1,4-dioxane (2.0 ml) of potassium acetate (76 mg, 0.772 mmol), bis (pinacolato) diboron (98 mg, 0.386 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (10.50 mg, 0.013 mmol) The medium mixture was heated in a sealed tube under N ₂ at 80 ° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a pad of silica gel and celite. The filtrate was concentrated to dryness to give the crude product as a tan foam which was used without further purification. LCMS (m / z, ES ⁺ ) = 639 (M + H ⁺ ).

Step 5: (4- (N- (2- (4-Chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-fluorophenyl) boronic acid Periodic acid Sodium (549 mg, 2.57 mmol) was added to 2- (4-chlorophenyl) -5-cyclopropyl-6- (N- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) phenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide (164 mg, 0.257 mmol) was added to a mixture in THF (6 mL) and 1N HCl (3.21 mL, 3.21 mmol). The mixture was stirred at room temperature overnight and EtOAc and water were added. The aqueous layer was extracted with EtOAc (2 times), the combined organic phases 10% Na ₂ S ₂ O ₃ solution, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to dryness. The residue was purified by reverse phase HPLC (MeCN / H ₂ O with 0.1% TFA) to give the title compound as a white solid (80 mg, 56%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.52 (q, 1 H) 8.23 (br. S., 1 H) 8.07 (s, 1 H) 7.94 (d, 2 H) 7.64 (d, 2 H) 7.55 (t, 1 H) 7.22 (s, 1 H) 7.11 (s, 1 H) 7.07-7.10 (m, 1 H) 3.45 (s, 4 H) 2.85 (d, 3 H) 2.04-2.15 ( m, 1 H) 1.00 (br. s., 1 H) 0.82 (d, 2 H) 0.54 (br. s., 1 H). LCMS (m / z, ES ⁺ ) = 557 (M + H +).

Example 8: 6- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) pyridin-3-ylboronic acid

Step 1: 6- (N- (5-Bromopyridin-2-yl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
To a solution of 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6-[(methylsulfonyl) amino] -1-benzofuran-3-carboxamide (400 mg, 1.00 mmol) in dimethylformamide (5 mL) At 0 ° C., lithium bis (trimethylsilyl) amide (1.5 mL, 1.50 mmol) was added. After 1 hour, 5-bromo-2-fluoropyridine (350 mg, 2.00 mmol) was added and stirring was maintained at 80 ° C. for 16 hours. The solution was cooled to room temperature, diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to give 6- (N- (5-bromopyridin-2-yl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran- 3-Carboxamide (430 mg, 0.775 mmol, 77.5% yield) was obtained as a yellow solid. LCMS (m / z, ES ⁺ ) = 559 (M + H ⁺ ).

Step 2: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) pyridin-2-yl) methylsulfonamido) benzofuran-3-carboxamide
6- (N- (5-bromopyridin-2-yl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (400 mg, 0.72 mmol), acetic acid A suspension of potassium (210 mg, 2.14 mmol), bis (pinacolato) diboron (2721 mg, 10.71 mmol), and PdCl ₂ (dppf) (58 mg, 0.071 mmol) in 1,4-dioxane (10 mL) was added to a thick-wall glass. The mixture was maintained at 90 ° C. for 16 hours with stirring in a pressure vessel. The solution was cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography to give 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (5- (4,4,5,5-tetramethyl -1,3,2-Dioxaborolan-2-yl) pyridin-2-yl) methylsulfonamido) benzofuran-3-carboxamide (320 mg, 0.53 mmol, 74% yield) was obtained as a white solid. LCMS (m / z, ES ⁺ ) = 606 (M + H ⁺ ).

Step 3: 6- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) pyridin-3-yl) boronic acid
5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridin-2-yl) methylsulfonamido) benzofuran-3-carboxamide (320 mg, 0.53 mmol), polymer-supported benzeneboronic acid (862 mg, 2.65 mmol) and 5N aqueous HCl (0.74 mL, 3.78 mmol) in tetrahydrofuran (10 mL) The suspension was stirred at room temperature for 48 hours. The solution was filtered, concentrated to dryness and purified by reverse phase HPLC to give 6- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl). Methylsulfonamido) pyridin-3-yl) boronic acid (80 mg, 0.153 mmol, 29% yield) was obtained as a white solid. ¹ H NMR (300 MHz, methanol-d ₄ ) δ 8.36 (s, 1H), 7.72 (m, 3H), 7.57 (s, 1H), 7.25 -7.1 (m, 3H), 6.90-6.87 (m, 1H ), 3.59 (s, 3H), 3.03 (s, 3H), 2.13-2.09 (m, 1H), 1.07 -1.03 (m, 2H), 0.70 (m, 2H). LCMS (m / z, ES +) = 524 (M + H +).

Example 9: (4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (difluoromethyl) phenyl) Boronic acid

Step 1: 2- (Difluoromethyl) -4-fluoro-1-nitrobenzene Diethylaminosulfur trifluoride (0.78 mL, 5.91 mmol) and 5-fluoro-2-nitrobenzaldehyde (1 g, 5.91 mmol) in dichloromethane (30 mL) Slowly added to the medium 0 ° C solution. The reaction mixture was stirred at 0 ° C. for 10 min, room temperature for 2.5 h, cooled to 0 ° C. and quenched by the slow addition of saturated aqueous NaHCO ₃ solution. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated to give 2- (difluoromethyl) -4-fluoro-1-nitrobenzene (1.13 g, quantitative) as a brown liquid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.26 (dd, 1 H), 7.60 (dd, 1 H), 7.28-7.56 (m, 2 H).

Step 2: 5-cyclopropyl-6- (N- (3- (difluoromethyl) -4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 2- (difluoromethyl) -4-fluoro-1 A solution of nitrobenzene (1.13 g, 5.91 mmol) and K ₂ CO ₃ (0.85 g, 6.15 mmol) in HMPA (6.2 mL) was stirred at 60 ° C. for 15 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-80% EtOAc / hexanes) to give the title compound (1.45 g, 97%). Obtained as a yellow solid. LCMS (m / z, ES ⁺ ) = 574.3 (M + H ⁺ ).

Step 3: 6- (N- (4-amino-3- (difluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-Cyclopropyl-6- (N- (3- (difluoromethyl) -4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (1.45 g, 2.53 mmol) and 10% Pd / C (catalytic) in MeOH (15 mL) was stirred under a hydrogen atmosphere (20 psi) for 3 h. The reaction mixture was filtered through celite, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (0.87 g, 63%) as a white solid. LCMS (m / z, ES ⁺ ) = 544.3 (M + H ⁺ ).

Step 4: 6- (N- (4-Bromo-3- (difluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide Nitrous acid Sodium (0.12 g, 1.75 mmol) was added to 6- (N- (4-amino-3- (difluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methyl. Benzofuran-3-carboxamide (0.87 g, 1.59 mmol) was added to a 0 ° C. solution in acetonitrile (10 ml) and aqueous HBr (48%) (10 mL). The reaction mixture was stirred at 0 ° C. for 30 min and copper (I) bromide (0.27 g, 1.91 mmol) was added. The reaction mixture was stirred at 75 ° C. for 2 hours and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (0.38 g, 39%). Obtained as a white foam. LCMS (m / z, ES ⁺ ) = 607, 609 (M + H ⁺ ).

Step 5: (4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (difluoromethyl) phenyl) boron acid
6- (N- (4-Bromo-3- (difluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.20 g, 0.33 mmol), potassium acetate (0.13 g, 1.32 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (0.027 g, 0.033 mmol), and bis (pinacolato) diboron (0.25 g, 0.99 mmol) The solution in dioxane (4.12 ml) was degassed, purged with nitrogen and heated at 80 ° C. for 3 hours 45 minutes. The reaction mixture was diluted with EtOAc and water, filtered through celite and evaporated. The brown residue was dissolved in THF (10 mL), and 1M HCl (5 mL). NaIO ₄ (0.56 g, 2.63 mmol) was added and the suspension was stirred for 1 h and diluted with EtOAc and water. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by reverse phase chromatography (5-100% CH ₃ CN / H ₂ O (0.1% formic acid)). To give the title compound (0.085 g, 45%) as a white solid. ¹ H NMR (400 MHz, methanol-d4) δ ppm 7.90-7.97 (m, 2 H), 7.87 (s, 1 H), 7.43-7.61 (m, 3 H), 7.30 (s, 1 H), 7.21 -7.29 (m, 2 H), 6.65-7.01 (m, 1 H), 3.33 (s, 3 H), 2.94 (s, 3 H), 2.08-2.21 (m, 1 H), 0.35-1.10 (m , 4 H). LCMS (m / z, ES ⁺ ) = 573.3 (M + H +).

Example 10: (4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (trifluoromethyl) phenyl Boronic acid

Step 1: 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (4-nitro-3- (trifluoromethyl) phenyl) methylsulfonamido) benzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 4-fluoro-1-nitro-2- (tri A solution of fluoromethyl) benzene (1.04 g, 4.97 mmol), K ₂ CO ₃ (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirred at 60 ° C. for 15 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (1.37 g, 93%). Obtained as an orange solid. LCMS (m / z, ES ⁺ ) = 592.2 (M + H ⁺ ).

Step 2: 6- (N- (4-amino-3- (trifluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (4-nitro-3- (trifluoromethyl) phenyl) methylsulfonamido) benzofuran-3-carboxamide (1.37 g, A solution of 2.31 mmol) and 10% Pd / C (catalytic) in MeOH (23 mL) was stirred under a hydrogen atmosphere (10 psi) for 1 hour. The reaction mixture was filtered through celite, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (1.3 g, quantitative) as a white solid. LCMS (m / z, ES ⁺ ) = 562.3 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-3- (trifluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide Sodium nitrate (0.18 g, 2.55 mmol) was added to 6- (N- (4-amino-3- (trifluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N -Methylbenzofuran-3-carboxamide (1.3 g, 2.32 mmol) was added to a 0 ° C. solution in acetonitrile (14 ml) and aqueous HBr (48%) (14 mL). The reaction mixture was stirred at 0 ° C. for 30 min and copper (I) bromide (0.40 g, 2.78 mmol) was added. The reaction mixture was stirred at 60 ° C. for 1 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (1.06 g, 73%). Obtained as a white foam. LCMS (m / z, ES ⁺ ) = 625.2, 627.2 (M + H ⁺ ).

Step 4: (4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (trifluoromethyl) phenyl) Boronic acid
6- (N- (4-Bromo-3- (trifluoromethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.20 g, 0.32 mmol), potassium acetate (0.13 g, 1.28 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (0.026 g, 0.032 mmol), bis (pinacolato) diboron (0.24 g, 0.96 mmol) 1,4 The solution in dioxane (4 ml) was degassed, purged with nitrogen and heated at 80 ° C. for 4 hours. The reaction mixture was diluted with EtOAc and water, filtered through celite and evaporated. The brown residue was dissolved in THF (10 mL), and 1M HCl (5 mL). NaIO ₄ (0.64 g, 3.20 mmol) was added and the suspension was stirred for 3 hours and diluted with EtOAc and water. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by reverse phase chromatography (5-100% CH ₃ CN / H ₂ O (0.1% formic acid)). To give the title compound (0.092 g, 49%) as a white solid. ¹ H NMR (400 MHz, methanol-d4) δ ppm 7.85-8.00 (m, 3 H), 7.59-7.72 (m, 2 H), 7.47 (d, 1 H), 7.29-7.34 (m, 1 H) , 7.20-7.29 (m, 2 H), 3.35 (s, 3 H), 2.94 (s, 3 H), 2.12 (tt, 1 H), 0.28-1.10 (m, 4 H). LCMS (m / z, ES ⁺ ) = 591.3 (M + H +).

Example 11: (4- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2,6-difluorophenyl) boron acid

Step 1: 5-cyclopropyl-6- (N- (3,5-difluoro-4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 1,3,5-trifluoro-2-nitrobenzene A solution of (0.91 g, 5.11 mmol), K ₂ CO ₃ (1.06 g, 7.67 mmol) in HMPA (7 mL) was stirred at 50 ° C. for 8 hours. Further 1,3,5-trifluoro-2-nitrobenzene (0.91 g, 5.11 mmol) was added and the reaction mixture was stirred at 50 ° C. for an additional 15 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was dissolved in 1: 1 CH ₂ Cl ₂ : acetone. The desired isomer precipitated and was collected by vacuum filtration and dried to give the title compound (0.92 g, 65%) as a white solid. LCMS (m / z, ES ⁺ ) = 560.2 (M + H).

Step 2: 6- (N- (4-amino-3,5-difluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-Cyclopropyl-6- (N- (3,5-difluoro-4-nitrophenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.65 g, 1.16 mmol ) And tin (II) chloride (0.66 g, 3.49 mmol) in EtOAc (10 mL) and ethanol (10 mL) were heated to reflux for 2 hours. The reaction mixture was diluted with EtOAc and water and the suspension was filtered through celite. The organic layer was dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (0.34 g, 55%) as a white solid. . LCMS (m / z, ES ⁺ ) = 530.2 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-3,5-difluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide sodium nitrite (0.034 g, 0.49 mmol) 6- (N- (4-amino-3,5-difluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran- 3-Carboxamide (0.235 g, 0.444 mmol) was added to a 0 ° C. solution in acetonitrile (3 ml) and aqueous HBr (48%) (3 mL). The reaction mixture was stirred at 0 ° C. for 30 min and copper (I) bromide (0.076 g, 0.53 mmol) was added. The reaction mixture was stirred at 90 ° C. for 2 hours and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (0.094 g, 36%). Obtained as a white foam. LCMS (m / z, ES ⁺ ) = 593.2, 595.2 (M + H ⁺ ).

Step 4: (4- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2,6-difluorophenyl) boronic acid
6- (N- (4-Bromo-3,5-difluorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.093 g, 0.157 mmol ), Potassium acetate (0.062 g, 0.627 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (0.013 g, 0.016 mmol), bis (pinacolato) diboron (0.080 g, 0.31 mmol) in 1,4-dioxane The solution in (1.6 ml) was degassed, purged with nitrogen and heated at 90 ° C. for 4 hours. The reaction mixture was diluted with EtOAc and water, filtered through celite and evaporated. The brown residue was dissolved in THF (5 mL) and 1M HCl (2.5 mL). NaIO ₄ (0.27 g, 1.25 mmol) was added and the suspension was stirred for 2.5 hours and diluted with EtOAc and water. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by reverse phase chromatography (5-100% CH ₃ CN / H ₂ O (0.1% formic acid)). To give the title compound (0.017 g, 19%) as a white solid. ¹ H NMR (400 MHz, methanol-d4) δ ppm 7.91-7.98 (m, 2 H), 7.79 (s, 1 H), 7.34 (s, 1 H), 7.20-7.29 (m, 2 H), 6.82 -6.92 (m, 2 H), 3.38 (s, 3 H), 2.95 (s, 3 H), 2.01-2.11 (m, 1 H), 0.70-1.07 (m, 3 H), 0.54 (br. S ., 1 H). LCMS (m / z, ES ⁺ ) = 559.3 (M + H +).

Example 12: (2-Cyano-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid

Step 1: 6- (N- (3-cyano-4-nitrophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-Fluoro-2-nitrobenzonitrile (1.280 mL, 11.18 mmol), 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (3.0 g , 7.45 mmol) and K ₂ CO ₃ (3.09 g, 22.36 mmol) in 1,2-dimethoxyethane (30 mL) and water (7.5 mL) were heated in a sealed tube to 80 ° C. overnight. This was cooled to room temperature, diluted with EtOAc, filtered and the off-white solid was washed with water and then dried in vacuo to give the crude desired product as a yellow solid (purity 80%, 3.9g, 76%). LCMS (m / z, ES ⁺ ) = 549 (M + H ⁺ ).

Step 2: 6- (N- (4-Amino-3-cyanophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
A solution of Na ₂ S ₂ O ₄ (7.24 g, 41.6 mmol) in water (70 mL) at room temperature under N _{2 is} 6- (N- (3-cyano-4-nitrophenyl) methylsulfonamide) -5 -Cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (3.8 g, 6.93 mmol) was added dropwise to a solution in THF. The mixture was stirred overnight. H ₂ O was added to the mixture and then extracted with EtOAc. The combined extracts were washed with brine and dried over Na ₂ SO ₄ . After concentration, the crude residue was purified by chromatography on silica gel eluting with 0-20% EtOAc in DCM to give the desired product as a white solid (2.67 g, 74.3%). LCMS (m / z, ES ⁺ ) = 519 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-3-cyanophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
tBuNO ₂ (0.859 ml, 7.23 mmol) was added dropwise to a solution of CuBr ₂ (1.292 g, 5.79 mmol) in acetonitrile (10 mL). The mixture was heated to 50 ° C. for 10 minutes and then 6- (N- (4-amino-3-cyanophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran- A suspension of 3-carboxamide (1.5 g, 2.89 mmol) in acetonitrile (40 mL) was added in portions to the above solution. This was stirred at 50 ° C. for 30 minutes and then cooled to room temperature. The reaction was quenched with ice-cold 1N HCl and then extracted with EtOAc. The combined extracts were washed with 10% Na ₂ S ₂ O ₃ and brine and then dried over Na ₂ SO ₄ . After concentration, the crude residue was purified by chromatography on silica gel eluting with 0-5% EtOAc in DCM to give the desired product as a white foam (1.18 g, 70%). LCMS (m / z, ES ⁺ ) = 583 (M + H ⁺ ).

Step 4: 6- (N- (3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) -5-cyclopropyl -2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-cyanophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (100 mg, 0.172 mmol), acetic acid Potassium (67.4 mg, 0.687 mmol), bis (pinacolato) diboron (87 mg, 0.343 mmol) and bis (tricyclohexylphosphine) palladium (II) dichloride (12.67 mg, 0.017 mmol) in 1,4-dioxane (2.0 ml) The medium mixture was kept at 90 ° C. overnight under N ₂ in a sealed tube. The mixture was cooled to room temperature, diluted with EtOAc, filtered through a pad of silica gel and celite, and then concentrated to dryness to give the crude product as a tan foam that was further purified without further purification. Used for step. LCMS (m / z, ES ⁺ ) = 630 (M + H ⁺ ).

Step 5: (2-Cyano-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid 6- (N- (3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide (108 mg, 0.172 mmol) was dissolved in tetrahydrofuran (4.0 mL). 1M HCl (2.059 mL, 1.029 mmol) was added followed by sodium periodate (294 mg, 1.373 mmol). The mixture was stirred overnight at room temperature. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 times). The organic phase was washed with 10% aqueous Na ₂ S ₂ O ₃ solution, brine and dried over Na ₂ SO ₄ . After concentration, the crude residue was purified by reverse phase HPLC (10-100% MeCN / H ₂ O with 0.1% TFA) to give the title compound as a white solid (58 mg, 62%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.60 (br. S., 1 H) 8.48 (q, 1 H) 8.12 (s, 1 H) 7.94-8.02 (m, 2 H) 7.73-7.80 (m, 2 H) 7.58-7.65 (m, 1 H) 7.41 (t, 2 H) 7.21 (s, 1 H) 3.46 (s, 3 H) 2.84 (d, 3 H) 2.03-2.14 (m, 1 H) 0.99 (br. S., 1 H) 0.85 (br. S., 2 H) 0.45 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 548 (M + H +).

Example 13: 6- (N- (4-borono-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid

Step 1: Ethyl 6-((4-bromo-3-chlorophenyl) amino) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylate
NEt ₃ (0.490 mL, 3.51 mmol) was added to a suspension of (4-bromo-3-chlorophenyl) boronic acid (364 mg, 1.546 mmol) in DCM (7 mL) and the resulting solution was equipped with a drying tube. In a flask, ethyl 6-amino-2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylate (500 mg, 1.405 mmol), acetic acid, with vigorous stirring in an open air at room temperature Copper (II) (281 mg, 1.546 mmol), 3 mol molecular sieves (1 g) and NEt ₃ (0.490 mL, 3.51 mmol) in DCM (7 mL) was added dropwise. After stirring at room temperature for 4 hours, a further solution of NEt ₃ (0.490 mL, 3.51 mmol) and (4-bromo-3-chlorophenyl) boronic acid (364 mg, 1.546 mmol) in DCM (7 mL) was added dropwise to the reaction mixture. This was followed by additional copper (II) acetate (281 mg, 1.546 mmol). The reaction mixture was stirred for 3 days and further a solution of NEt ₃ (0.490 mL, 3.51 mmol) and (4-bromo-3-chlorophenyl) boronic acid (364 mg, 1.546 mmol) in DCM (7 mL) was added dropwise, followed by acetic acid. Copper (II) (281 mg, 1.546 mmol) was added. After 2 hours, EtOAc was added followed by celite. The mixture was stirred for 30 minutes then filtered through a pad of celite and the brown solution was concentrated to dryness. EtOAc was added followed by water. The organic layer was separated, washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The crude product was purified on silica gel (hexane / EtOAc) to give ethyl 6-((4-bromo-3-chlorophenyl) amino) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylate. (685 mg, 1.231 mmol, 88% yield) was obtained as an orange foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.17 (s, 1 H), 7.98-8.07 (m, 2 H), 7.58-7.65 (m, 3 H), 7.49-7.56 (m, 2 H ), 7.11 (d, 1 H), 6.87 (dd, 1 H), 4.36 (q, 2 H), 1.95-2.12 (m, 1 H), 1.36 (t, 3 H), 0.93-1.05 (m, 2 H), 0.57-0.71 (m, 2 H).

Step 2: Ethyl 6- (N- (4-bromo-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylate
A 1M solution of LiHMDS in THF (1.049 mL, 1.049 mmol) was added to ethyl 6-((4-bromo-3-chlorophenyl) amino) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3 at −78 ° C. -Added dropwise to a solution of carboxylate (440 mg, 0.807 mmol) in THF (15 mL). After stirring for 45 minutes, the red solution was added dropwise at −78 ° C. to a solution of MsCl (0.252 mL, 3.23 mmol) in THF (1 mL) via cannula. When the addition was complete, the yellow solution was warmed to room temperature and stirred overnight. Water (150 mL) and EtOAc (150 mL) were added. The organic layer was separated, washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The crude product was purified on silica gel (hexane / EtOAc) to give ethyl 6- (N- (4-bromo-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran- 3-carboxylate (259 mg, 0.395 mmol, 49% yield) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.22 (s, 1 H), 8.05 (d, 2 H), 7.78 (d, 1 H), 7.64-7.71 (m, 3 H), 7.62 ( s, 1 H), 7.31 (dd, 1 H), 4.35 (q, 2 H), 3.46 (s, 3 H), 2.10-2.22 (m, 1 H), 1.34 (t, 3 H), 0.69- 1.13 (m, 3 H), 0.42 (br. S., 1 H).

Step 3: 6- (N- (4-Bromo-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid
A 1M solution of NaOH (1.877 mL, 1.877 mmol) was added to ethyl 6- (N- (4-bromo-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxy. To a solution of the rate (234 mg, 0.375 mmol) in THF (2 mL) and MeOH (1 mL) was added at room temperature. After 1 hour, a white precipitate formed, but the starting material is still evident by LCMS. THF (3 mL) and 4N NaOH solution (1 mL) were added and the mixture was heated to 60 ° C. for 4 h. EtOAc was added and 1N HCl was added to acidify the aqueous layer. The organic layer was separated, washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated to 6- (N- (4-bromo-3-chlorophenyl) methylsulfonamido) -2- (4 -Chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid (220 mg, 0.351 mmol, 94% yield) was obtained as a white solid. LCMS (m / z, ES ⁺ ) = 594.0 (MH).

Step 4: 6- (N- (3-Chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamide) -2- (4 -Chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid
6- (N- (4-Bromo-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid (100 mg, 0.168 mmol), 4,4,4 ′ , 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (85 mg, 0.336 mmol), potassium acetate (65.9 mg, 0.672 mmol) and PdCl ₂ A flask containing (dppf) -CH ₂ Cl ₂ adduct (13.72 mg, 0.017 mmol) is evacuated and purged with nitrogen (2 times), then 1,4-dioxane (4 mL) is added and the mixture is added to nitrogen. Under heating at 90 ° C. for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc, filtered through celite, and water was added. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was used as such for the next step.

Step 5: 6- (N- (4-borono-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid
6- (N- (3-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) -2- (4-chlorophenyl) A solution of -5-cyclopropylbenzofuran-3-carboxylic acid (110 mg, 0.171 mmol) and sodium periodate (183 mg, 0.856 mmol) in THF (14 mL) and 1N aqueous HCl (7 mL) was stirred at room temperature for 4 h. Then water and EtOAc were added. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by reverse phase HPLC (water / ACN + 0.1% formic acid) to give 6- (N- (4-borono-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5- Cyclopropylbenzofuran-3-carboxylic acid (24 mg, 0.041 mmol, 24% yield) was obtained as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.31 (br. S., 1 H), 8.33 (s, 2 H), 8.16 (s, 1 H), 8.03 (d, 2 H), 7.52 -7.70 (m, 3 H), 7.37-7.48 (m, 2 H), 7.34 (dd, 1 H), 3.40 (s, 3 H), 2.09-2.22 (m, 1 H), 0.64-1.11 (m , 3 H), 0.47 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 558.1 (MH).

Example 14: (4- (N- (3-carbamoyl-2- (4-chlorophenyl) -5-cyclopropylbenzofuran-6-yl) methylsulfonamido) -2-chlorophenyl) boronic acid

HATU (27.1 mg, 0.071 mmol) was added to 6- (N- (4-borono-3-chlorophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropylbenzofuran-3-carboxylic acid (20 mg, 0.036 mmol) and Hunig's base (0.031 mL, 0.179 mmol) in DMF (3 mL). After stirring at room temperature for 1 hour, a 2M solution of ammonia in MeOH (0.357 mL, 0.714 mmol) was added and the solution was stirred for 16 hours. Water and EtOAc were added. The organic layer was separated, washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by reverse phase HPLC (water / MeCN + 0.1% formic acid) to give (4- (N- (3-carbamoyl-2- (4-chlorophenyl) -5-cyclopropylbenzofuran-6-yl) Methylsulfonamido) -2-chlorophenyl) boronic acid (9 mg, 0.015 mmol, 43% yield) was obtained as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.33 (s, 2 H), 8.12 (s, 1 H), 8.05 (s, 1 H), 7.94-8.01 (m, 2 H), 7.80 ( s, 1 H), 7.59-7.68 (m, 2 H), 7.41-7.46 (m, 1 H), 7.39 (d, 1 H), 7.30-7.37 (m, 1 H), 7.23 (s, 1 H ), 3.41 (s, 3 H), 2.05-2.21 (m, 1 H), 1.02 (br. S., 1 H), 0.83 (br. S., 2 H), 0.53 (br. S., 1 H). LCMS (m / z, ES +) = 559.2 (M + H +).

Example 15: 6- (N- (7-chloro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamido) -5-cyclopropyl-2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide

Step 1: Methyl 5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrobenzoate
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (1.0 g, 2.49 mmol), methyl 5-fluoro-2-nitrobenzoate (0.99 g , 4.97 mmol), and potassium carbonate (1.03 g, 7.45 mmol) in HMPA (6.2 mL) were stirred at 60 ° C. for 3 days. The solution is diluted with EtOAc and water and the organic layer is washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-80% EtOAc / hexanes) to give the title The compound (1.33 g, 92%) was obtained as a yellow solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.99 (d, J = 9.09 Hz, 1 H), 7.85-7.92 (m, 2 H), 7.56 (s, 1 H), 7.53 (s, 1 H ), 7.50 (dd, J = 9.09, 2.64 Hz, 1 H), 7.43 (d, J = 2.64 Hz, 1 H), 7.19-7.26 (m, 2 H), 5.80 (d, J = 4.59 Hz, 1 H), 3.90 (s, 3 H), 3.34 (s, 3 H), 3.02 (d, J = 4.98 Hz, 3 H), 1.91 (tt, J = 8.37, 5.31 Hz, 1 H), 1.01 (br s., 1 H), 0.89 (br. s., 1 H), 0.73-0.85 (m, 1 H), 0.58 (br. s., 1 H).

Step 2: Methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate methyl 5- (N -(5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrobenzoate (1.33 g, 2.29 mmol) and 10% Pd / C A solution of (catalyst) in MeOH (20 mL) was stirred under a hydrogen atmosphere (15 psi) for 1.5 hours. The solution was filtered through celite and evaporated to give the title compound (1.26 g, quantitative) as a pale yellow solid, which was used without further purification.

Step 3: Methyl 2-amino-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate methyl 2-Amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate (1.60 g, 2.91 mmol) and NCS A solution of (0.39 g, 2.91 mmol) in CH ₃ CN (80 mL) was stirred at 40 ° C. for 30 minutes. Further NCS (0.39 g, 2.91 mmol) was added and the reaction mixture was heated at 40 ° C. for an additional 30 min, evaporated onto silica gel and purified by silica gel chromatography (0-70% EtOAc / hexanes) to give the title compound ( 1.29 g (76%) was obtained as a light pink solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.00 (d, J = 2.54 Hz, 1 H), 7.85-7.92 (m, 2 H), 7.71 (s, 1 H), 7.65 (d, J = 2.63 Hz, 1 H), 7.43 (s, 1 H), 7.15-7.22 (m, 2 H), 6.36 (br. S., 2 H), 5.85 (d, J = 4.78 Hz, 1 H), 3.87 (s, 3 H), 3.19 (s, 3 H), 2.98 (d, J = 4.88 Hz, 3 H), 2.15-2.30 (m, 1 H), 0.31-1.11 (m, 4 H).

Step 4: Methyl 2-bromo-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate Sodium nitrate (0.17 g, 2.42 mmol) was added to methyl 2-amino-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6- Yl) methylsulfonamido) benzoate (1.29 g, 2.20 mmol) in acetonitrile (7.3 ml) and 48% aqueous HBr solution (7.3 ml) at 0 ° C. at 0 ° C. and the reaction mixture is stirred at 0 ° C. for 30 minutes, Copper (I) bromide (0.38 g, 2.64 mmol) was added and the solution was heated at 50 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (1.24 g, 86%). Obtained as a white foam. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.86-7.93 (m, 2 H), 7.50-7.63 (m, 4 H), 7.17-7.25 (m, 2 H), 5.79 (br. S., 1 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 3.01 (d, J = 4.88 Hz, 3 H), 1.94-2.04 (m, 1 H), 0.76-1.09 (m, 3 H), 0.55 (br. S., 1 H).

Step 5: 6- (N- (4-Bromo-3-chloro-5-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methyl Benzofuran-3-carboxamide
LiBH ₄ (2.85 ml, 5.71 mmol) solution (2M in THF) was added to methyl 2-bromo-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methyl Carbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate (1.24 g, 1.90 mmol) was added dropwise to a 0 ° C. solution in tetrahydrofuran (THF) (13.5 ml) and methanol (1.3 ml). The reaction mixture was stirred at 0 ° C. for 1 h and quenched with 1M NaOH. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The crude alcohol was dissolved in THF (14 mL). DIEA (1.0 ml, 5.71 mmol) and MOM-Cl (0.36 ml, 4.76 mmol) were added and the reaction mixture was stirred at 50 ° C. overnight. Saturated NaHCO ₃ was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc / hexanes) to give the title compound (1.08 g, 85%). Obtained as a white foam. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.86-7.93 (m, 2 H), 7.61 (s, 1 H), 7.50 (d, 1 H), 7.49 (s, 1 H), 7.42 (d , J = 2.83 Hz, 1 H), 7.18-7.25 (m, 2 H), 5.80 (br. S., 1 H), 4.73 (s, 2 H), 4.62 (s, 2 H), 3.38 (s , 3 H), 3.27 (s, 3 H), 3.01 (d, J = 4.98 Hz, 3 H), 2.05-2.14 (m, 1 H), 0.75-1.11 (m, 3 H), 0.58 (br. s., 1 H).

Step 6: 6- (N- (7-chloro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamido) -5-cyclopropyl-2- ( 4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-chloro-5-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3 -Carboxamide (0.25 g, 0.38 mmol), potassium acetate (0.15 g, 1.50 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (0.031 g, 0.038 mmol), bis (pinacolato) diboron (0.29 g, 1.13 mmol) in 1,4-dioxane (3.75 ml) was degassed, purged with nitrogen and heated at 90 ° C. for 15 h. The reaction mixture was diluted with EtOAc and water, filtered through celite and evaporated. The brown residue was dissolved in THF (5 mL) and 1M HCl (5 mL) and the solution was heated at 70 ° C. for 4 h. MeOH (2 mL) was added and the solution was heated at 70 ° C. for an additional 15 hours and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (100% EtOAc to 10% MeOH / CH ₂ Cl ₂ ) to give the title compound as a clear oil Obtained as a thing. MeOH was added and the precipitate was collected by vacuum filtration, washed with MeOH and dried to give the title compound (0.0831 g, 39%) as a light tan solid. The filtrate was purified by reverse phase chromatography (5-100% CH ₃ CN / H ₂ O (0.1% formic acid)) to give a further batch of the title compound (0.0146 g, 7%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (s, 1 H), 8.50 (d, J = 4.68 Hz, 1 H), 8.09 (s, 1 H), 7.94-8.02 (m, 2 H ), 7.37-7.46 (m, 3 H), 7.28 (d, J = 1.56 Hz, 1 H), 7.22 (s, 1 H), 4.96 (s, 2 H), 3.47 (s, 3 H), 2.84 (d, J = 4.59 Hz, 3 H), 2.02-2.14 (m, 1 H), 0.98 (br. s., 1 H), 0.82 (br. s., 2 H), 0.49 (br. s. , 1 H). LCMS (m / z, ES ⁺ ) = 569.2 (M + H +).

Example 16: (4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (methylsulfonyl) phenyl) Boronic acid

Step 1: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (methylthio) -4-nitrophenyl) methylsulfonamido) benzofuran-3-carboxamide
6- (N- (3-chloro-4-nitrophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (2 g, 3.58 mmol), and A mixture of sodium thiomethoxide (0.685 g, 9.78 mmol) was dissolved in 1: 1 CH ₃ CN / isopropanol (20 mL) and stirred at room temperature for 3 hours. The solvent was evaporated and water (60 mL) was added. The yellowish solid that formed was filtered and washed with water to give a pale yellow solid that was used in the next step (1.6 g, 86%). LCMS (m / z, ES ⁺ ) = 570 (M + H ⁺ ).

Step 2: 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (methylsulfonyl) -4-nitrophenyl) methylsulfonamido) benzofuran-3-carboxamide acetic acid ( 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (methylthio) -4-nitrophenyl) methylsulfonamido) benzofuran-3-carboxamide (1 g) , 1.756 mmol) was carefully added H ₂ O ₂ (1.630 mL, 15.96 mmol). The reaction mixture was stirred at 90 ° C. for 5 hours. The resulting yellow suspension was concentrated, cooled in an ice bath and saturated NaHCO ₃ was added. The resulting yellow solid was filtered, washed 3 times with water (3 x 15 mL) and dried. This material was used in the next step. (0.8g, 83%). LCMS (m / z, ES ⁺ ) = 602 (M + H ⁺ ).

Step 3: 6- (N- (4-amino-3- (methylsulfonyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (methylsulfonyl) -4-nitrophenyl) methylsulfonamido) benzofuran-3-carboxamide (0.7 g, 1.164 To a solution of mmol) in 1: 1 EtOH / ethyl acetate (10 mL) was added tin (II) chloride (1.324 g, 6.98 mmol). The reaction was heated at 70 ° C. for 3 hours. The solvent was evaporated and the reaction was partitioned between EtOAc and water. The obtained semi-viscous material was filtered (6 hours), and the obtained solid (0.5 g, 75%) was directly carried on to the next step. LCMS (m / z, ES ⁺ ) = 572 (M + H ⁺ ).

Step 4: 6- (N- (4-Bromo-3- (methylsulfonyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-amino-3- (methylsulfonyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.4 g, 0.700 mmol) in acetonitrile (3 mL) was added 8M HBr (0.437 mL, 3.50 mmol). The resulting solution was cooled in an ice-water bath for 15 minutes and the mixture was treated with a solution of sodium nitrite (0.072 g, 1.050 mmol) in water (2 mL) over 5 minutes. The resulting yellow suspension was stirred in an ice bath for 1.5 hours and then treated with copper (I) bromide (0.201 g, 1.399 mmol) in portions over 5 minutes. The dark brown solution was warmed to 60 ° C. and stirring was continued for another 2 hours. The mixture was cooled to room temperature and poured into a mixture of 5% aqueous sodium bisulfite (6 mL) and EtOAc (80 mL). The phases were separated and the aqueous solution was further extracted twice with EtOAc (15 mL). The combined EtOAc solution was washed with 5% aqueous sodium bisulfite, saturated aqueous sodium bicarbonate, saturated brine, dried over sodium sulfate and concentrated to dryness under reduced pressure to give a yellow foam. This material was subjected to flash chromatography (silica gel, 9: 1 hexane / EtOAc to EtOAc gradient) to give the title compound (0.3 g, 68%). LCMS (m / z, ES ⁺ ) = 635, 637 (M + H ⁺ ).

Step 5: (4- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- (methylsulfonyl) phenyl) boron acid
6- (N- (4-Bromo-3- (methylsulfonyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (200 mg, 0.315 mmol ) In 1,4-dioxane (2 mL), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) ) (400 mg, 1.574 mmol), potassium acetate (154 mg, 1.574 mmol) and Pd (II) (dppf) Cl ₂ DCM complex (12.85 mg, 0.016 mmol) were added. The mixture was stirred at 80 ° C. under nitrogen. After 4 hours, the mixture was cooled to room temperature and diluted with EtOAc (10 mL). The resulting solution was washed with water, saturated brine and dried over sodium sulfate. After evaporation of the solvent, the crude residue was dissolved in THF (10 mL) and the resulting solution was cooled in an ice-water bath. The solution was treated with 1N aqueous HCl (1.574 mL, 1.574 mmol) followed by sodium periodate (135 mg, 0.629 mmol). The mixture was stirred at 0 ° C. for 20 minutes and then warmed to room temperature. After 18 hours, the mixture was partitioned between water and EtOAc and the phases were separated. The aqueous solution was extracted with EtOAc. The combined EtOAc solution was washed with 5% aqueous sodium bisulfite solution, saturated brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was subjected to HPLC purification (ACN: water-0.1% formic acid) to give the pure product (12 mg, 6.4%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.97 (br. S., 2H), 7.87 (d, J = 5.37 Hz, 2H), 7.56-7.64 (m, 2H), 7.49 (s, 1H) , 7.15-7.24 (m, 2H), 6.15-6.37 (m, 1H), 5.77-5.92 (m, 1H), 3.30 (s, 3H), 3.13 (br. S., 3H), 3.00 (d, J = 2.34 Hz, 3H), 1.91-2.10 (m, 1H), 1.18-1.34 (m, 1H), 0.95-1.10 (m, 1H), 0.83-0.93 (m, 1H), 0.69-0.83 (m, 1H ), 0.44-0.61 (m, 1H). LCMS (m / z, ES ⁺ ) = 601 (M + H +).

Example 17: 1- (2-chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl)- 4-Methyl-2,6,7-trioxa-1-borabicyclo [2.2.2] octane-1-ido potassium salt

(2-Chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) boronic acid (0.0750 g, 0.135 mmol) and 1,1,1-tris (hydroxymethyl) ethane (0.0180 g, 0.148 mmol) in a stirred solution of anhydrous THF (6 mL) was added activated 3 angstrom molecular sieves (0.400 g). The resulting mixture was heated to reflux for 4 hours and cooled to room temperature. The mixture was filtered to remove solids and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in anhydrous THF (5 mL) and the solution was cooled to 0 ° C. The solution was treated by dropwise addition of 1M potassium t-butoxide / THF (135 μL, 0.135 mmol). After warming to room temperature, the solution was concentrated to dryness under reduced pressure to give the title compound as a pale yellow solid in quantitative yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 8.48 (d, J = 4.0 Hz, 1 H) 8.09 (s, 1 H) 7.98 (dd, J = 8.9, 5.5 Hz, 2 H) 7.51 (d, J = 7.9 Hz, 1 H) 7.39 (t, J = 8.9 Hz, 2 H) 7.07-7.18 (m, 3 H) 3.55 (s, 6 H) 3.28 (s, 3 H) 2.82 (d, J = 3.4 Hz, 3 H) 2.10-2.23 (m, 1 H) 0.73-1.04 (m, 4 H) 0.45 (s, 3 H).

Example 18: ((4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenoxy) methyl) boronic acid

Step 1: 6- (N- (4- (benzyloxy) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (0.500 g, 1.24 mmol), (4- (benzyloxy) phenyl) boronic acid ( 0.567 g, 2.49 mmol), copper (II) acetate (0.451 g, 2.49 mmol), and triethylamine (1.00 mL, 7.12 mmol) in DCM (25 mL) was added to a powder of 3 angstrom molecular sieves (1.00 g). Processed. The resulting mixture was stirred at room temperature using a drying tube under air to remove moisture. After 18 hours, the mixture was further treated with (4- (benzyloxy) phenyl) boronic acid (250 mg) and stirring was continued at room temperature. After an additional 8 hours, the mixture was filtered through celite and the filtrate was concentrated to dryness under reduced pressure. The black residue was suspended in EtOAc and the undissolved solid was removed by filtration through celite. The filtrate was concentrated to dryness under reduced pressure and the residue was subjected to flash chromatography (silica gel, DCM to 1: 1 DCM / EtOAc gradient elution) to give the title compound (0.403 g, 56%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 8.39-8.47 (m, 1 H) 8.12-8.18 (m, 1 H) 7.92-7.99 (m, 2 H) 7.55 (d, J = 8.9 Hz, 2 H) 7.28-7.46 (m, 7 H) 7.13 (s, 1 H) 7.03 (d, J = 9.0 Hz, 2 H) 5.09 (s, 2 H) 3.29 (s, 3 H) 2.82 (d, J = 4.5 Hz, 3 H) 2.25-2.35 (m, 1 H) 0.75-1.14 (m, 3 H) 0.32-0.58 (m, 1 H). LCMS (m / z, ES ⁺ ) = 585 (M + H +).

Step 2: 5-cyclopropyl-2- (4-fluorophenyl) -6- (N- (4-hydroxyphenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide
6- (N- (4- (benzyloxy) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.174 g, 0.298 mmol) A solution in 1THF / EtOH (20 mL) was subjected to hydrogenation at 40 psi in the presence of 5% palladium on charcoal (20 mg). After 3 hours, the reaction vessel was purged with nitrogen, the catalyst was removed by filtration through celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was triturated with DCM / hexane. The resulting solid was collected by filtration and dried in vacuo to give the title compound (144 mg, 98%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 9.67 (br. S., 1 H) 8.44 (q, J = 4.4 Hz, 1 H) 8.13 (s, 1 H) 7.97 (dd, J = 8.9, 5.4 Hz, 2 H) 7.46 (d, J = 8.9 Hz, 2 H) 7.40 (t, J = 8.9 Hz, 2 H) 7.12 (s, 1 H) 6.77 (d, J = 8.9 Hz, 2 H) 3.27 (s, 3 H) 2.83 (d, J = 4.6 Hz, 3 H) 2.28-2.39 (m, 1 H) 0.76-1.11 (m, 3 H) 0.47 (br. s., 1 H). LCMS (m / z, ES ⁺ ) = 495 (M + H +).

Step 3: ((4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenoxy) methyl) boronic acid
5-cyclopropyl-2- (4-fluorophenyl) -6- (N- (4-hydroxyphenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide (85.0 mg, 0.172 mmol), potassium carbonate (0.119 g, 0.859 mmol), and 2- (bromomethyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.152 g, 0.688 mmol) in MeCN (3 mL) in a sealed tube. And heated to 65 ° C. with stirring. After 2 hours, the mixture was cooled to room temperature, filtered to remove solids, and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to RP-HPLC purification (C18, MeCN / water / 0.1% formic acid) followed by lyophilization from MeCN / water to give the title compound (77 mg, 81%) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 8.40-8.47 (m, 1 H) 8.15 (s, 1 H) 8.03 (s, 2 H) 7.97 (dd, J = 8.8, 5.4 Hz, 2 H) 7.53 (d, J = 9.0 Hz, 2 H) 7.40 (t, J = 8.9 Hz, 2 H) 7.12 (s, 1 H) 6.90 (d, J = 9.1 Hz, 2 H) 3.58 (s, 2 H) 3.33 (s, 3 H) 2.82 (d, J = 4.5 Hz, 3 H) 2.24-2.38 (m, 1 H) 0.76-1.10 (m, 3 H) 0.47 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 553 (M + H +).

Example 19: ((2-Chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenoxy) methyl) Boronic acid

Step 1: 6- (N- (4- (benzyloxy) -3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (1.00 g, 2.49 mmol), (4- (benzyloxy) -3-chlorophenyl) A mixture of boronic acid (1.31 g, 4.97 mmol), copper (II) acetate (0.903 g, 4.97 mmol), and triethylamine (2.00 mL, 14.4 mmol) in anhydrous DCM (25 mL) was added to a powder of 3 angstrom molecular sieves (2.00 Treated with g). The resulting mixture was stirred at room temperature using a drying tube under air to remove moisture. After 18 hours, the mixture was further treated with (4- (benzyloxy) -3-chlorophenyl) boronic acid (1.00 g). After an additional 18 hours, the mixture was diluted with DCM (15 mL) and (4- (benzyloxy) -3-chlorophenyl) boronic acid (1.30 g), copper (II) acetate (0.900 g), 3 angstrom molecular sieves (2.00 g) and triethylamine (2 mL). After an additional 16 hours, the mixture was filtered through celite to remove solids and the filtrate was concentrated to dryness under reduced pressure. The residue was suspended in EtOAc and the undissolved solid was removed by filtration through celite. The filtrate was washed with water (2 times), brine (1 time), dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude was purified by flash chromatography (silica gel, DCM to 7: 3 DCM / EtOAc gradient), then recrystallized from hexane / EtOAc to give the title compound (0.83 g, 54%) as an off-white solid. Obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 8.40-8.47 (m, 1 H) 8.20 (s, 1 H) 7.93-8.00 (m, 2 H) 7.69 (d, J = 2.6 Hz, 1 H) 7.52 (dd, J = 8.9, 2.7 Hz, 1 H) 7.30-7.48 (m, 7 H) 7.25 (d, J = 9.1 Hz, 1 H) 7.14 (s, 1 H) 5.21 (s, 2 H) 3.33 (s, 3 H) 2.82 (d, J = 4.6 Hz, 3 H) 2.17-2.33 (m, 1 H) 0.75-1.09 (m, 3 H) 0.42 (br. s., 1 H). LCMS (m / z, ES ⁺ ) = 619, 621 (M + H +).

Step 2: 6- (N- (3-Chloro-4-hydroxyphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4- (benzyloxy) -3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.300 g, 0.485 mmol ) In anhydrous DCM (12 mL) was cooled in an ice-water bath and treated with 1M BCl ₃ / DCM (2.00 mL, 2.00 mmol). After stirring in an ice bath for 10 minutes, the solution was warmed to room temperature. This solution was then combined with the solution obtained from the same 50 mg scale reaction and poured into stirred ice water (50 mL). The mixture was diluted with EtOAc (50 mL), stirred vigorously for several minutes and the phases separated. The EtOAc solution was washed with water (2 times), brine (1 time), dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude was subjected to flash chromatography (silica gel, DCM to 1: 1 DCM / EtOAc gradient) followed by recrystallization from hexane / EtOAc to give the title compound (0.110 g, 37%) as a white powder. Fractions containing impurities from the above chromatography were combined, concentrated and subjected to RP-HPLC purification (C18, MeCN / water / 0.1% formic acid) to total additional title compound (0.107 g, 36%). Yield was 73%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 10.45 (s, 1 H) 8.40-8.48 (m, 1 H) 8.18 (s, 1 H) 7.90-8.01 (m, 2 H) 7.61 (d, J = 2.6 Hz, 1 H) 7.34-7.45 (m, 3 H) 7.14 (s, 1 H) 6.96 (d, J = 8.8 Hz, 1 H) 3.30 (s, 3 H) 2.82 (d, J = 4.6 Hz , 3 H) 2.20-2.34 (m, 1 H) 0.77-1.09 (m, 3 H) 0.43 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 529 (M + H +).

Step 3: ((2-Chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenoxy) methyl) boron acid
6- (N- (3-chloro-4-hydroxyphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (65.0 mg, 0.123 mmol), Mixture of potassium carbonate (85.0 mg, 0.614 mmol) and 2- (bromomethyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.109 g, 0.492 mmol) in anhydrous MeCN (4 mL) Was heated to 65 ° C. with stirring in a sealed tube. After 2 hours, the mixture was cooled to room temperature, filtered to remove solids, and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to RP-HPLC purification (C18, MeCN / water / 0.1% formic acid) and then lyophilized from MeCN / water to give the title compound (43 mg, 60%) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 8.40-8.47 (m, 1 H) 8.20 (s, 1 H) 8.05 (s, 2 H) 7.97 (dd, J = 8.7, 5.5 Hz, 2 H) 7.65 (d, J = 2.5 Hz, 1 H) 7.53 (dd, J = 8.9, 2.6 Hz, 1 H) 7.40 (t, J = 8.8 Hz, 2 H) 7.14 (s, 1 H) 7.00 (d, J = 9.1 Hz, 1 H) 3.73 (s, 2 H) 3.32 (s, 3 H) 2.82 (d, J = 4.5 Hz, 3 H) 2.20-2.35 (m, 1 H) 0.90 (br. S., 3 H) 0.45 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 587 (M + H +).

Example 20: 5-Cyclopropyl-2- (4-fluorophenyl) -6- (N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfone Amido) -N-methylbenzofuran-3-carboxamide

Step 1: Methyl 5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrobenzoate methyl 5-fluoro- 2-nitrobenzoate (2.138 g, 10.73 mmol), 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (4.0 g, 9.94 mmol) and A mixture of K ₂ CO ₃ (4.12 g, 29.8 mmol) in hexamethylphosphoramide (25 mL) was stirred in a sealed tube at 60 ° C. for 3 days. Upon cooling to room temperature, the mixture was diluted with EtOAc and then filtered through a pad of celite. The filtrate was washed with water and brine and dried over Na ₂ SO ₄ . Concentrated under reduced pressure and the residue was purified by flashing chromatography on silica gel eluting with 0-50% EtOAc in hexanes to give the product (3.2 g, 55%) as a yellow solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.00 (d, J = 9.17 Hz, 1 H) 7.89 (dd, J = 8.78, 5.27 Hz, 2 H) 7.55 (d, J = 9.37 Hz, 2 H ) 7.50 (dd, J = 9.07, 2.63 Hz, 1 H) 7.44 (d, J = 2.73 Hz, 1 H) 7.23 (t, J = 8.68 Hz, 2 H) 5.81 (d, J = 4.49 Hz, 1 H) ) 3.91 (s, 3 H) 3.35 (s, 3 H) 3.02 (d, J = 4.88 Hz, 3 H) 1.86-1.96 (m, 1 H) 0.97-1.05 (m, 1 H) 0.89 (br. S ., 2 H) 0.59 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 582 (M + H +).

Step 2: Methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate methyl 5- (N -(5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrobenzoate (3.2 g, 5.50 mmol) in methanol (50 mL) Dissolved and hydrogenated at room temperature in the presence of 10% Pd / C (0.586 g, 0.550 mmol) under H ₂ (H ₂ balloon). The mixture was stirred for 6 hours and then filtered by passing it through a pad of celite. Concentrated under reduced pressure and rinsed twice with hexanes to give the desired product (3.0 g, 98%) as a yellow solid that was used in the next step without further purification. LCMS (m / z, ES ⁺ ) = 552 (M + H ⁺ ).

Step 3: Methyl 2-bromo-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate methyl 2-amino- 5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate (1.6 g, 2.70 mmol) in acetonitrile (30 mL) and A suspension in hydrogen bromide (25 mL, 2.70 mmol) was treated with aqueous sodium nitrite (0.205 g, 2.97 mmol) at 0 ° C., the mixture was stirred for 30 minutes, and copper (I) bromide (0.464 g) was stirred. 3.24 mmol) was added in portions at the same temperature. This was warmed to room temperature and then heated to 55 ° C. overnight. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was washed with brine and dried over Na ₂ SO ₄ . Concentrated under reduced pressure and the residue was purified by flashing chromatography on silica gel eluting with 0-50% EtOAc in hexanes to give the product (0.92 g, 55%) as a white foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.49 (q, J = 4.23 Hz, 1 H) 8.14 (s, 1 H) 7.97 (dd, J = 8.78, 5.46 Hz, 2 H) 7.80 (d , J = 2.93 Hz, 1 H) 7.75 (d, J = 8.78 Hz, 1 H) 7.50 (dd, J = 8.88, 2.83 Hz, 1 H) 7.41 (t, J = 8.88 Hz, 2 H) 7.22 (s , 1 H) 3.84 (s, 3 H) 3.44 (s, 3 H) 2.84 (d, J = 4.68 Hz, 3 H) 2.05-2.15 (m, 1 H) 0.92-1.05 (br. S, 1 H) 0.87 (br. S., 2 H) 0.40 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 617 (M + H +).

Step 4: 6- (N- (4-Bromo-3- (hydroxymethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
LiBH ₄ (1.593 mL, 3.19 mmol) solution (2 M in THF) was added to methyl 2-bromo-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3 at 0 ° C. under N _2. -(Methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate (0.76 g, 1.062 mmol) was added dropwise to a solution of tetrahydrofuran (6.0 mL) and methanol (0.600 mL). The mixture was stirred at the same temperature for 3 hours. This was quenched with 1M NaOH and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 times). The organic phase was washed with brine and dried over Na ₂ SO ₄ . This was concentrated to dryness to give the crude product (> 99%) as a tan foam which was used in the next step without further purification. LCMS (m / z, ES ⁺ ) = 587 (M + H ⁺ ).

Step 5: 6- (N- (4-Bromo-3-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3- carboxamide chloro (methoxy) methane (0.201mL, 2.65mmol) and, N ₂ under, 6- (N-(4-bromo-3- (hydroxymethyl) phenyl) methyl sulfonamide) -5-cyclopropyl-2- ( 4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.724 g, 1.06 mmol) and DIEA (0.555 mL, 3.18 mmol) were added dropwise to a solution of tetrahydrofuran (10 mL). The mixture was heated to 50 ° C. overnight. Cool to room temperature, add aqueous NaHCO ₃ and extract the aqueous layer with EtOAc (twice). The organic phase was washed with brine and dried over Na ₂ SO ₄ . The crude residue was purified by chromatography on silica gel eluting with 0-50% EtOAc in hexanes to give the product (0.65 g, 97%) as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.90 (dd, J = 8.78, 5.27 Hz, 2 H) 7.64 (s, 1 H) 7.57 (d, J = 2.73 Hz, 1 H) 7.50 (d, J = 8.78 Hz, 1 H) 7.47 (s, 1 H) 7.18-7.26 (m, 3 H) 5.79 (d, J = 4.49 Hz, 1 H) 4.74 (s, 2 H) 4.61 (s, 2 H) 3.39 (s, 3 H) 3.25 (s, 3 H) 3.01 (d, J = 4.88 Hz, 3 H) 2.08-2.18 (m, 1 H) 0.75-1.14 (m, 3 H) 0.58 (br. S. , 1 H). LCMS (m / z, ES ⁺ ) = 633 (M + H +).

Step 6: 5-Cyclopropyl-2- (4-fluorophenyl) -6- (N- (3-((methoxymethoxy) methyl) -4- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) phenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (200 mg , 0.317 mmol), potassium acetate (124 mg, 1.267 mmol), bis (pinacolato) diboron (161 mg, 0.633 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (25.9 mg, 0.032 mmol) The mixture in dioxane (3.0 ml) was kept at 90 ° C. overnight under N ₂ in a sealed tube. Cool the mixture to room temperature, dilute with EtOAc, filter through a pad of silica gel and celite, then concentrate to dryness to give the crude product as a tan foam, which is the next step without further purification. Used for. LCMS (m / z, ES ⁺ ) = 679 (M + H ⁺ ).

Step 7: (4- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-((methoxymethoxy) methyl) Phenyl) boronic acid Crude 5-cyclopropyl-2- (4-fluorophenyl) -6- (N- (3-((methoxymethoxy) methyl) -4- (4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl) phenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide (215 mg, 0.317 mmol) was dissolved in methanol (1.0 mL) and tetrahydrofuran (4.0 mL). HCl (4.0 mL, 4.00 mmol) was added, followed by sodium periodate (542 mg, 2.54 mmol). The mixture was stirred overnight at room temperature. This was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 times). The organic phase was washed with 10% aqueous Na ₂ S ₂ O ₃ solution, brine and dried over Na ₂ SO ₄ . Concentrated under reduced pressure and the residue was purified by reverse phase HPLC (10-100 MeCN / H ₂ O with 0.05% TFA) to give the product (54 mg, 29%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.47 (q, J = 4.36 Hz, 1 H) 8.07 (s, 1 H) 7.97 (dd, J = 8.88, 5.37 Hz, 2 H) 7.31-7.53 (m, 5 H) 7.14-7.20 (m, 1 H) 4.65 (s, 2 H) 4.59 (s, 2 H) 3.37 (s, 2 H) 3.24 (s, 2 H) 2.83 (d, J = 4.68 Hz, 3 H) 2.11-2.26 (m, 1 H) 1.01 (br. S., 1 H) 0.84 (br. S., 2 H) 0.52 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 597 (M + H +).

Step 8: 5-Cyclopropyl-2- (4-fluorophenyl) -6- (N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamide ) -N-Methylbenzofuran-3-carboxamide
HCl (1.0 mL, 1.000 mmol) was added to (4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2- To a solution of ((methoxymethoxy) methyl) phenyl) boronic acid (53 mg, 0.089 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.2 mL). The mixture was heated to 70 ° C. overnight under N ₂ . Cooled to room temperature and then evaporated to dryness under reduced pressure to give the desired product (46 mg, 97%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.20 (br. S., 1 H) 8.49 (q, J = 4.42 Hz, 1 H) 8.06 (s, 1 H) 7.97 (dd, J = 8.98 , 5.46 Hz, 2 H) 7.71 (d, J = 8.19 Hz, 1 H) 7.48 (s, 1 H) 7.35-7.44 (m, 3 H) 7.19 (s, 1 H) 4.96 (s, 2 H) 3.42 (s, 3 H) 2.84 (d, J = 4.68 Hz, 3 H) 2.09-2.21 (m, 1 H) 0.99 (br. s., 1 H) 0.81 (d, J = 5.27 Hz, 2 H) 0.50 (br. s., 1 H). LCMS (m / z, ES ⁺ ) = 535 (M + H +).

Example 21: (4- (N- (2- (4-chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-cyanophenyl) boronic acid

Step 1: 2- (4-Chlorophenyl) -6- (N- (3-cyano-4-nitrophenyl) methylsulfonamido) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
5-fluoro-2-nitrobenzonitrile (0.656 mL, 5.73 mmol), 2- (4-chlorophenyl) -5-cyclopropyl-N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (2.0 g, A mixture of 4.77 mmol) and K ₂ CO ₃ (1.980 g, 14.32 mmol) in 1,2-dimethoxyethane (20 mL) and water (5.0 mL) was heated to 80 ° C. overnight in a sealed tube. Cool to room temperature and dilute with EtOAc. The mixture was washed with water and brine and dried over Na ₂ SO ₄ . This was concentrated to dryness to give the crude product (> 99%) as a yellow solid which was used in the next step without further purification. LCMS (m / z, ES ⁺ ) = 565 (M + H ⁺ ).

Step 2: 6- (N- (4-Amino-3-cyanophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
A solution of Na ₂ S ₂ O ₄ (4.98 g, 28.6 mmol) in water (50 mL) was added 2- (4-chlorophenyl) -6- (N- (3-cyano-4-nitrophenyl) at room temperature under N _2. ) Methylsulfonamido) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide (2.70 g, 4.77 mmol) was added dropwise to a solution in THF. The mixture was stirred overnight. Further water was added and then extracted with EtOAc. The combined extracts were washed with brine and dried over Na ₂ SO ₄ . Concentrated under reduced pressure and the crude residue was purified by chromatography on silica gel eluting with 0-15% EtOAc in DCM to give the product (2.3 g, 83%) as a white solid. LCMS (m / z, ES ⁺ ) = 535 (M + H ⁺ ).

Step 3: 6- (N- (4-Bromo-3-cyanophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
tBuNO ₂ (0.611 ml, 5.14 mmol) was added dropwise to a solution of CuBr ₂ (0.918 g, 4.11 mmol) in acetonitrile (5 mL). The mixture was heated to 50 ° C. for 10 minutes and then 6- (N- (4-amino-3-cyanophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3 A suspension of carboxamide (1.1 g, 2.056 mmol) in acetonitrile (25 mL) was added in portions to the above mixture. This was stirred at 50 ° C. for 30 minutes and then cooled to room temperature. It was quenched with ice-cold HCl (1N) and then extracted with EtOAc. The combined extracts are washed with 10% Na ₂ S ₂ O ₃ and brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue is flushed on silica gel eluting with 0-5% EtOAc in DCM. Purification by chromatography gave the product (0.64 g, 52%) as a pale yellow foam. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.84 (d, J = 8.59 Hz, 2 H) 7.58-7.64 (m, 3 H) 7.47-7.53 (m, 4 H) 5.80 (d, J = 4.29 Hz, 1 H) 3.28 (s, 3 H) 3.03 (d, J = 4.88 Hz, 3 H) 1.91-2.00 (m, 1 H) 0.72-1.11 (m, 3 H) 0.55 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 600 (M + H +).

Step 4: 2- (4-Chlorophenyl) -6- (N- (3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methyl Sulfonamide) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-cyanophenyl) methylsulfonamido) -2- (4-chlorophenyl) -5-cyclopropyl-N-methylbenzofuran-3-carboxamide (150 mg, 0.250 mmol), potassium acetate A mixture of (98 mg, 1.002 mmol), bis (pinacolato) diboron (127 mg, 0.501 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (20.5 mg, 0.025 mmol) in 1,4-dioxane (3 ml). And maintained at 90 ° C. for 3 hours under N _{2 in} a sealed tube. LCMS (UV254) showed 47% desired product and 53% corresponding boronic acid (probably produced on LC?). Cool the mixture to room temperature, dilute with EtOAc, filter through a pad of silica gel and celite, then concentrate to dryness to give the crude product (> 99%) as a pale yellow foam, which is further purified. Used for next step without. LCMS (m / z, ES ⁺ ) = 646 (M + H ⁺ ).

Step 5: (4- (N- (2- (4-Chlorophenyl) -5-cyclopropyl-3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-cyanophenyl) boronic acid Crude 2 -(4-Chlorophenyl) -6- (N- (3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamide)- 5-Cyclopropyl-N-methylbenzofuran-3-carboxamide (162 mg, 0.251 mmol) was dissolved in tetrahydrofuran (6.0 mL). HCl (3.01 mL, 1.505 mmol) was added followed by sodium periodate (429 mg, 2.006 mmol). The mixture was stirred overnight at room temperature. This was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 times). The organic phase was washed with 10% aqueous Na ₂ S ₂ O ₃ solution and brine and dried over Na ₂ SO ₄ . Concentrated under reduced pressure and the residue was purified by reverse phase HPLC (10-100 MeCN / H ₂ O with 0.05% TFA) to give the product (88 mg, 62%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.54-8.74 (br.s., 1 H) 8.51 (q, J = 4.49 Hz, 2 H) 8.13 (s, 1 H) 7.93 (d, J = 8.78 Hz, 2 H) 7.74-7.79 (m, 2 H) 7.58-7.67 (m, 3 H) 7.22 (s, 1 H) 3.47 (s, 3 H) 2.84 (d, J = 4.68 Hz, 3 H ) 2.03-2.14 (m, 1 H) 0.99 (br. S., 1 H) 0.85 (br. S., 2 H) 0.45 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 564 (M + H +).

Example 22: 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-methyl-4- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) phenyl) methylsulfonamido) benzofuran-3-carboxamide

Step 1: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-methyl-4-nitrophenyl) methylsulfonamido) benzofuran-3-carboxamide
6- (N- (3-chloro-4-nitrophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (2.5 g, 4.48 mmol) and To a mixture of DABAL-Me ₃ (1.366 g, 5.38 mmol) in dry tetrahydrofuran (10 mL), under a nitrogen atmosphere, Pd ₂ (dba) ₃ (0.041 g, 0.045 mmol) and xanthophos (0.052 g, 0.090 mmol) were added, The reaction was refluxed at 100 ° C. for 0.5 hour. The reaction mixture was filtered through celite and washed with methanol (50 mL). After evaporating the solvent, the crude was redissolved in DCM and washed with water. DCM was dried over anhydrous Na ₂ SO ₄ and evaporated to give the title compound as a yellow solid in 82% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.02 (d, J = 9.2 Hz, 1H), 7.86-7.93 (m, 2H), 7.55 (d, J = 1.8 Hz, 2H), 7.17- 7.27 (m, 4H), 5.80 (d, J = 4.5 Hz, 1H), 3.22-3.44 (m, 3H), 3.02 (d, J = 4.9 Hz, 3H), 2.47-2.66 (m, 3H), 1.88 -2.11 (m, 1H), 1.03 (br. S., 1H), 0.89 (d, J = 7.2 Hz, 2H), 0.62 (br. S., 1H). LCMS (m / z, ES ⁺ ) = 538 (M + H +).

Step 2: 6- (N- (4-amino-3-methylphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide ethanol (10 mL) and 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-methyl-4-nitrophenyl) methylsulfonamido) benzofuran-3-carboxamide (2.0 mL in THF (2 mL) g, 3.72 mmol) was added Pd / C (0.396 g) and subjected to hydrogenation at room temperature for 12 hours. The reaction mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound in 86% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.85-7.95 (m, 1H), 7.67-7.73 (m, 1H), 7.37-7.42 (m, 1H), 7.11-7.26 (m, 1H) , 6.59-6.68 (m, 1H), 5.86 (br. S., 1H), 3.18 (s, 1H), 2.99 (s, 2H), 2.10-2.17 (m, 1H), 1.37-1.51 (m, 1H ), 1.08-1.19 (m, 1H), 0.91-1.06 (m, 1H), 0.45-0.92 (m, 1H). LCMS (m / z, ES ⁺ ) = 508 (M + H +).

Step 3: 5-cyclopropyl-2- (4-fluorophenyl) -6- (N- (4-iodo-3-methylphenyl) methylsulfonamido) -N-methylbenzofuran-3-carboxamide
6- (N- (4-amino-3-methylphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (1.0 g, 1.97 mmol) To p-TsOH (1.12 g, 5.91 mmol) in t-butanol (2 mL) at 5 ° C. and stirred for 10 min. A mixture of sodium nitrite (0.272 g, 3.94 mmol) and KI (0.818 g, 4.93 mmol) in water (1 mL) was then added to the reaction mixture. Stir at the same temperature for 15 minutes, bring to room temperature and heat at 60 ° C. for 15 minutes. Water, sodium bicarbonate solution and sodium thiosulfate solution (20 mL) were added sequentially. The resulting precipitate was filtered and dried to give the title compound as a yellow solid in 83% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.84-7.97 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.58-7.67 (m, 1H), 7.47 (s, 1H ), 7.26 (br. S., 1H), 7.22 (t, J = 8.6 Hz, 2H), 6.92-7.05 (m, 1H), 5.79 (br. S., 1H), 3.25 (s, 3H), 3.02 (d, J = 4.9 Hz, 3H), 2.39 (s, 3H), 0.96 (d, J = 6.8 Hz, 2H), 0.85 (br.s., 2H), 0.61 (br.s., 1H) . LCMS (m / z, ES ⁺ ) = 618 (M + H +).

Step 4: 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-methyl-4- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) phenyl) methylsulfonamido) benzofuran-3-carboxamide bis (pinacolato) diboron (103 mg, 0.404 mmol), [bis (diphenylphosphino) ferrocene] dichloropalladium (III) complex (33.0 mg, 0.040 mmol) and potassium acetate (39.7 mg, 0.404 mmol) under a nitrogen atmosphere, 5-cyclopropyl-2- (4-fluorophenyl) -6- (N- (4-iodo-3-methylphenyl) methylsulfonamide ) -N-methylbenzofuran-3-carboxamide (50 mg, 0.081 mmol) and 1,4-dioxane (2 mL) were added, and the mixture was stirred at 80 ° C. for 12 hours. Product and deiodinated product were formed in a ratio of 80:20. The mixture was diluted with water and extracted with ethyl acetate (20 mL). The ethyl acetate solution was dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude was purified by RP-HPLC (ACN / water / 0.1% formic acid) to give the title compound in 5% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.44-8.56 (m, 1H), 7.90-8.05 (m, 3H), 7.60 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 8.9 Hz, 2H), 7.12-7.25 (m, 3H), 6.77 (s, 0H), 2.84 (d, J = 4.5 Hz, 3H), 2.42 (s, 3H), 1.28 (s, 12H), 0.98 (br. s., 1H), 0.79 (br. s., 2H), 0.51 (br. s., 1H). LCMS (m / z, ES ⁺ ) = 619 (M + H +).

Example 23: (2-Chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenethyl) boronic acid

Step 1: 6- (N- (3-chloro-4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) phenyl) methylsulfonamide) -5-Cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (3-chloro-4-vinylphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (200 mg, 0.371 mmol) in THF (2 mL) suspension in bis (1,5-cyclooctadiene) diiridium (I) dichloride (6.2 mg, 0.0091 mmol) and diphenylphosphinobutane (7.9 mg, 0.019 mmol) in THF (2. In 2 mL). After 10 minutes, pinacol borane (1M in THF) (1.1 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 3 days. The solvent was evaporated and the residue was subjected to silica gel chromatography using dichloromethane: methanol to give 6- (N- (3-chloro-4- (2- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) ethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (60%) (158 mg) Got. This material was used in the next step without further purification. LCMS (m / z, ES ⁺ ) = 667 (M + H ⁺ ).

Step 2: (2-Chloro-4- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenethyl) boronic acid Periodate Sodium acid (722 mg, 3.37 mmol) and 1N aqueous HCl (2.70 mL, 2.70 mmol) were added to 6- (N- (3-chloro-4- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (150 mg, 0.225 mmol) in THF ( 3 mL) was added to the medium cold (0 ° C.) solution. The mixture was stirred at 0 ° C. for 10 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate. The organic layer was separated and washed with 5% aqueous sodium thiosulfate and brine and dried over sodium sulfate. The solvent was evaporated and the residue was subjected to reverse phase HPLC (C18, acetonitrile: water with 0.1% formic acid) to give the title compound (33 mg, 25%) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.41-8.51 (m, 1 H) 8.14 (s, 1 H) 7.92-8.02 (m, 2 H) 7.59 (s, 2 H) 7.46-7.51 ( m, 1 H) 7.35-7.44 (m, 3 H) 7.29-7.35 (m, 1 H) 7.17 (s, 1 H) 3.37 (s, 3 H) 2.79-2.87 (m, 3 H) 2.62-2.74 ( m, 2 H) 2.11-2.24 (m, 1 H) 0.93-1.09 (m, 1 H) 0.75-0.93 (m, 4 H) 0.46 (m, 1 H). LCMS (m / z, ES ⁺ ) = 585 (M + H +).

Example 24: 5-cyclopropyl-6- (N- (7-fluoro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamide) -2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide

Step 1: Methyl 5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluoro-2-nitrobenzoate
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (1.850 g, 4.60 mmol), methyl 3,5-difluoro-2-nitrobenzoate ( A mixture of 1.996 g, 9.19 mmol) and Na ₂ CO ₃ (1.462 g, 13.79 mmol) in hexamethylphosphoramide (25 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and filtered through a pad of Celite®. The filtrate was washed with brine, dried over Na ₂ SO ₄ , concentrated, purified by silica gel chromatography (0-35% EtOAc in hexanes) and methyl 5- (N- (5-cyclopropyl-2- ( 4-Fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluoro-2-nitrobenzoate (1.61 g, 58% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 0.62 (br. S., 1 H), 0.79-0.95 (m, 2 H), 0.96-1.11 (m, 1 H), 1.84-1.97 (m, 1 H), 3.01 (d, J = 5.0 Hz, 3 H), 3.31-3.36 (m, 3 H), 3.87 (s, 3 H), 5.82 (d, J = 4.6 Hz, 1 H), 7.22 ( t, J = 8.6 Hz, 2 H), 7.37-7.44 (m, 1 H), 7.50-7.54 (m, 2 H), 7.56 (s, 1 H), 7.83-7.92 (m, 2 H). LCMS (m / z, ES ⁺ ) = 600.2 (M + H +).

Step 2: Methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorobenzoate methyl 5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluoro-2-nitrobenzoate (810 mg, 1.351 mmol ) And Pd / C (10 wt%, 144 mg, 0.135 mmol) was stirred in THF (10.0 mL) and MeOH (5.0 mL) overnight under hydrogen (1 atm). The mixture was filtered through a 45 μm disk and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- ( Methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorobenzoate (601 mg, 78% yield) was obtained as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 0.81-1.11 (m, 3 H), 2.14-2.26 (m, 1 H), 2.91-3.03 (m, 3 H), 3.19 (s, 3 H) , 3.86 (s, 3 H), 5.80 (d, J = 4.5 Hz, 1 H), 5.88 (br. S., 2 H), 7.15-7.25 (m, 2 H), 7.40 (dd, J = 12.1 , 2.5 Hz, 1 H), 7.44 (s, 1 H), 7.70 (s, 1 H), 7.80 (dd, J = 2.4, 1.5 Hz, 1 H), 7.84-7.94 (m, 2 H). LCMS (m / z, ES +) = 570.3 (M + H +).

Step 3: Methyl 2-bromo-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorobenzoate methyl 2-Amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorobenzoate (601 mg, 1.055 mmol ) In acetonitrile (6 mL) and concentrated HBr (6 mL, 48% aqueous solution) was cooled in an ice-water bath and then treated with a solution of sodium nitrite (95 mg, 1.372 mmol) in water (1 mL). After 15 minutes, copper (I) bromide (182 mg, 1.266 mmol) was added to the mixture. The mixture was then heated to 50 ° C. After 30 minutes, the solution was cooled to room temperature and diluted with EtOAc. Sodium bisulfate (15 mL, 5% aqueous solution) and saturated aqueous NaHCO ₃ solution (20 mL) were added to the solution. The organic phase was separated, washed with brine (40 mL), dried over Na ₂ SO ₄ , concentrated, then purified by silica gel chromatography (0-35% EtOAc in hexanes) to give methyl 2-bromo-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -3-fluorobenzoate (430 mg, 64% yield) as a white solid Got as. ¹ H NMR (400 MHz, chloroform-d) δ ppm 0.55 (br. S., 1 H), 0.75-0.93 (m, 2 H), 0.97 (d, J = 6.6 Hz, 1 H), 1.88-2.04 (m, 1 H), 3.01 (d, J = 4.9 Hz, 3 H), 3.28 (s, 3 H), 3.91 (s, 3 H), 5.72-5.85 (m, 1 H), 7.21 (t, J = 8.6 Hz, 2 H), 7.33 (dd, J = 10.0, 2.8 Hz, 1 H), 7.49 (dd, J = 2.8, 1.3 Hz, 1 H), 7.52 (s, 1 H), 7.58 (s , 1 H), 7.85-7.92 (m, 2 H). LCMS (m / z, ES +) = 633, 635 (M + H +).

Step 4: 6- (N- (4-Bromo-3-fluoro-5- (hydroxymethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3 -Carboxamide
A solution of LiBH ₄ (1.018 mL, 2M) in THF was added at 0 ° C. with methyl 2-bromo-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran- 6-yl) methylsulfonamido) -3-fluorobenzoate (430 mg, 0.679 mmol) was added dropwise to a solution in MeOH (0.5 mL) and THF (5.0 mL). After 0.5 hour, citric acid (4.0 mL, 5 wt%) was added to the mixture. The organic solvent was then removed under reduced pressure. The residue was diluted with DCM (10 mL), washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered and concentrated to 6- (N- (4-bromo-3-fluoro- 5- (Hydroxymethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (400 mg, 97% yield) was obtained as a white solid. The crude was used in the next step without further purification. ¹ H NMR (400 MHz, chloroform-d) δ ppm 0.57 (br. S., 1 H), 0.71-0.88 (m, 2 H), 0.93-1.06 (m, 1 H), 1.96-2.02 (m, 1 H), 2.63 (t, J = 6.1 Hz, 1 H), 2.96 (d, J = 4.8 Hz, 3 H), 3.25 (s, 3 H), 4.67 (d, J = 5.6 Hz, 2 H) , 5.96 (d, J = 4.8 Hz, 1 H), 7.08-7.21 (m, 3 H), 7.31 (s, 1 H), 7.42 (s, 1 H), 7.56 (s, 1 H), 7.82 ( dd, J = 8.7, 5.3 Hz, 2 H). LCMS (m / z, ES +) = 605, 607 (M + H +).

Step 5: 6- (N- (4-Bromo-3-fluoro-5-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methyl Benzofuran-3-carboxamide
6- (N- (4-Bromo-3-fluoro-5- (hydroxymethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide ( A mixture of 350 mg, 0.578 mmol), DIPEA (0.303 mL, 1.734 mmol) and MOM-Cl (0.110 mL, 1.445 mmol) in THF (3.0 mL) was stirred at 50 ° C. in a sealed tube. After 23 hours, the solution was concentrated and purified by silica gel chromatography (0-40% EtOAc in hexanes) to give 6- (N- (4-bromo-3-fluoro-5-((methoxymethoxy) methyl) phenyl). ) Methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (303 mg, 70% yield) was obtained. ¹ H NMR (400 MHz, chloroform-d) δ ppm 0.59 (br. S., 1 H), 0.74-0.94 (m, 2 H), 0.94-1.10 (m, 1 H), 1.99-2.12 (m, 1 H), 3.00 (d, J = 4.9 Hz, 3 H), 3.27 (s, 3 H), 3.37 (s, 3 H), 4.61 (s, 2 H), 4.71 (s, 2 H), 5.85 (d, J = 4.6 Hz, 1 H), 7.13 (dd, J = 10.0, 2.7 Hz, 1 H), 7.17-7.25 (m, 2 H), 7.33 (d, J = 1.5 Hz, 1 H), 7.48 (s, 1 H), 7.58 (s, 1 H), 7.83-7.92 (m, 2 H). LCMS (m / z, ES +) = 649, 651 (M + H +).

Step 6: 5-Cyclopropyl-6- (N- (3-fluoro-5-((methoxymethoxy) methyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-fluoro-5-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3 - carboxamide (300 mg, 0.462 mmol), bis (pinacolato) diboron (293mg, 1.155mmol), potassium acetate (181mg, 1.848mmol) and _{PdCl 2 (dppf) -CH 2 Cl} 2 adduct (37.7 mg, 0.046 mmol) The mixture in 1,4-dioxane (4.0 mL) was stirred overnight at 90 ° C. in a sealed tube under N ₂ . The mixture was cooled to room temperature, diluted with EtOAc, filtered through a pad of silica gel and Celite®, then concentrated to dryness to give the crude product (306 mg) (68% of the title compound, deborylated byproduct). 26%) was obtained and used in the next step without further purification. LCMS (m / z, ES +) = 697 (M + H ⁺ ).

Step 7: 5-Cyclopropyl-6- (N- (7-fluoro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamide) -2- ( 4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide Hydrochloric acid aqueous solution (4 mL, 1N) was added to 5-cyclopropyl-6- (N- (3-fluoro-5-((methoxymethoxy) methyl) -4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (306 mg ) In THF (4.0 mL) and MeOH (0.8 mL). The mixture was heated to 70 ° C. overnight under N ₂ . The mixture was cooled to room temperature and the organic solvent was removed under reduced pressure. The crude was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. MeOH (6 mL) was then added to the crude and stirred for 15 minutes. A white solid formed which was filtered to give the crude product (170 mg, 90% purity). The crude product (50 mg) was purified by silica gel chromatography (0-100% EtOAc in DCM, then 0-10% MeOH in DCM) to give 5-cyclopropyl-6- (N- (7-fluoro-1- Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (17 mg, yield 6.24 %). Further crude product (120 mg) was washed with MeOH, dried and 5-cyclopropyl-6- (N- (7-fluoro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] Oxabolol-5-yl) methylsulfonamido) -2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (106 mg, yield 36.6%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.50 (br. S., 1 H), 0.81 (br. S., 2 H), 0.97 (br. S., 1 H), 2.06 (br. s., 1 H), 2.84 (d, J = 4.3 Hz, 3 H), 3.48 (s, 3 H), 4.95 (s, 2 H), 7.02 (d, J = 9.9 Hz, 1 H), 7.20 (d, J = 7.9 Hz, 2 H), 7.41 (t, J = 8.8 Hz, 2 H), 7.97 (dd, J = 8.5, 5.6 Hz, 2 H), 8.04 (s, 1 H), 8.49 ( d, J = 4.5 Hz, 1 H), 9.28 (s, 1 H). LCMS (m / z, ES +) = 553 (M + H +).

Example 25: 6- (N- (3-chloro-4- (2-hydroxy-1,2-oxaborolan-4-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) ) -N-Methylbenzofuran-3-carboxamide

Step 1: 6- (N- (3-Chloro-4- (3-hydroxyprop-1-en-2-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl)- N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (327 mg, 0.552 mmol), allyl alcohol (0.475 mL, 6.9 mmol), palladium acetate (II) (29 mg, 0.132 mmol), 1,3-bis (diphenylphosphino) propane (108 mg, 0.26 mmol) and triethylamine (0.7 mL, 4.9 mmol) in DMSO (2 mL) ) And 1-butyl-3-methylimidazolium tetrafluoroborate (2 mL) was heated in a sealed tube at 135 ° C. for 59 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel (hexane: ethyl acetate) gave 6- (N- (3-chloro-4- (3-hydroxyprop-1-en-2-yl) phenyl) methylsulfonamido) -5-cyclopropyl -2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide (75 mg, 24%) was obtained. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.84-7.97 (m, 2 H) 7.60 (s, 1 H) 7.48 (s, 1 H) 7.37-7.41 (m, 1 H) 7.29-7.32 (m , 1 H) 7.28 (s, 1 H) 7.16-7.24 (m, 3 H) 5.77-5.97 (m, 1 H) 5.51-5.63 (m, 1 H) 5.17 (s, 1 H) 4.34-4.46 (m , 2 H) 3.28 (s, 3 H) 3.00 (d, J = 4.88 Hz, 3 H) 2.1 (m, 1 H) 0.99-1.10 (m, 1 H) 0.77-0.93 (m, 2 H) 0.48- 0.73 (m, 1 H). LCMS (m / z, ES ⁺ ) = 569 (M + H +).

Step 2: 6- (N- (3-Chloro-4- (3- (methoxymethoxy) prop-1-en-2-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluoro Phenyl) -N-methylbenzofuran-3-carboxamide methyl chloromethyl ether (0.024 mL, 0.321 mmol) was replaced with 6- (N- (3-chloro-4- (3-hydroxyprop-1-en-2-yl) (Phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (83 mg, 0.146 mmol) and DIEA (0.076 mL, 0.438 mmol) in dichloromethane (2 mL) Added to the mixture. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, concentrated and 6- (N- (3-chloro-4- (3- (methoxymethoxy) prop-1-ene- 2-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide was obtained as a white foam (76 mg, 85%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.89 (dd, J = 8.78, 5.27 Hz, 2 H) 7.60 (s, 1 H) 7.48 (s, 1 H) 7.38 (d, J = 2.15 Hz, 1 H) 7.26-7.31 (m, 1 H) 7.16-7.24 (m, 2 H) 5.77-5.94 (m, 1 H) 5.56 (s, 1 H) 5.31 (s, 1 H) 5.22 (s, 1 H ) 4.65 (s, 2 H) 4.34 (s, 2 H) 3.33 (s, 3 H) 3.27 (s, 3 H) 3.00 (d, J = 4.88 Hz, 3 H) 1.87-2.29 (m, 1 H) 0.14-1.47 (m, 4 H). LCMS (m / z, ES ⁺ ) = 613 (M + H +).

Step 3: 6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-4-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide bis (1,5-cyclooctadiene) diiridium (I) dichloride (2.054 mg, 3.06 μmol) and diphenylphosphinobutane (2.61 mg, 6.12 μmol) in THF under nitrogen Dissolved in (1 mL). 6- (N- (3-Chloro-4- (3- (methoxymethoxy) prop-1-en-2-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl)- A solution of N-methylbenzofuran-3-carboxamide (75 mg, 0.122 mmol) in THF (1 mL) was added. After stirring for 10 minutes, pinacol borane (1M in THF) (0.367 mL, 0.367 mmol) was added and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was subjected to silica gel chromatography using hexane: EtOAc to give a mixture containing the title compound (47%). To this material was added THF (1 mL) and 1N aqueous HCl (1 mL, 1.00 mmol). After heating at 70 ° C. for 18 hours, the solvent was evaporated and the residue was purified by reverse phase HPLC (C18, acetonitrile: water with 0.1% formic acid) to give the title compound (7.8 mg, 10.2%) as a white solid. Obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.71 (s, 1 H) 8.41-8.50 (m, 1 H) 8.11 (s, 1 H) 7.90-8.01 (m, 2 H) 7.32-7.52 ( m, 5 H) 7.17 (s, 1 H) 4.12-4.27 (m, 1 H) 3.62-3.83 (m, 2 H) 3.39 (s, 3 H) 2.82 (d, J = 4.69 Hz, 3 H) 2.09 -2.22 (m, 1 H) 1.17-1.32 (m, 1 H) 0.92-1.06 (m, 2 H) 0.72-0.90 (m, 2 H) 0.46 (m, 1 H). LCMS (m / z, ES ⁺ ) = 597 (M + H +).

Example 26: (3- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenethyl) boronic acid

Step 1: Ethyl 6-((3-bromophenyl) amino) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3-carboxylate ethyl 6-amino-5-cyclopropyl-2- (4- Fluorophenyl) benzofuran-3-carboxylate (1.00 g, 2.95 mmol), (3-bromophenyl) boronic acid (1.184 g, 5.89 mmol), copper (II) acetate (0.803 g, 4.42 mmol), triethylamine (1.232 mL) , 8.84 mmol) and 4A molecular sieves (2 g) were stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc and filtered through celite. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane: EtOAc) to give ethyl 6-((3-bromophenyl) amino) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran. -3-Carboxylate (740 mg, 51%) was obtained. LCMS (m / z, ES ⁺ ) = 494, 496 (M + H, M + 2).

Step 2: Ethyl 6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3-carboxylate Lithium bis (trimethylsilyl) amide solution in THF 1M) (1.93 mL, 1.93 mmol) at -78 ° C. with ethyl 6-((3-bromophenyl) amino) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3-carboxylate (734 mg, 1.48 mmol) in THF (10 mL) was added dropwise. The mixture was stirred for 45 min and then a solution of methanesulfonyl chloride (0.463 mL, 5.94 mmol) in THF (1.5 mL) was added at -78 ° C. After the addition was complete, the reaction mixture was warmed to room temperature overnight. Water and EtOAc were added. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane: EtOAc) to give ethyl 6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3- Carboxylate (318 mg, 37%) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.20 (s, 1 H) 8.03-8.13 (m, 2 H) 7.62-7.66 (m, 1 H) 7.59 (s, 1 H) 7.43 (s, 4 H) 7.30-7.39 (m, 1 H) 4.26-4.41 (m, 2 H) 3.42 (s, 3 H) 2.12-2.26 (m, 1 H) 1.28-1.37 (m, 3 H) 0.71-1.14 ( m, 4 H) 0.41 (m, 1 H). LCMS (m / z, ES ⁺ ) = 572, 574 (M + H, M + 2).

Step 3: 6- (N- (3-Bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3-carboxylic acid lithium hydroxide monohydrate (68.5 mg, 1.630 mmol) of ethyl 6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3-carboxylate (311 mg, 0.543 mmol) in THF: MeOH : Added to suspension in water / 3: 1: 1 (10 mL). The mixture was stirred overnight at room temperature. The mixture was acidified with 2N aqueous HCl and the volatile solvent was evaporated. The residue was partitioned between EtOAc and water. The organic layer is washed with brine, dried over sodium sulfate, concentrated, and 6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3. -Carboxylic acid (309 mg, quantitative) was obtained as a yellow solid. ¹ H NMR (400 MHz, chloroform-d) δppm 8.01-8.13 (m, 2 H) 7.77 (s, 1 H) 7.66 (s, 1 H) 7.54 (t, J = 1.95 Hz, 1 H) 7.39 (dd , J = 8.21, 1.37 Hz, 1 H) 7.30-7.36 (m, 1 H) 7.17-7.26 (m, 3 H) 3.27 (s, 3 H) 2.11 (s, 1 H) 0.74-1.18 (m, 3 H) 0.48-0.74 (m, 1 H). LCMS (m / z, ES ⁺ ) = 544, 546 (M + H, M + 2).

Step 4: 6- (N- (3-Bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
HATU (237 mg, 0.624 mmol) was added to 6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) benzofuran-3-carboxylic acid (283 mg, 0.520 mmol). To a solution of methylamine hydrochloride (70.2 mg, 1.040 mmol) and DIEA (0.318 mL, 1.819 mmol) in DMF (2 mL) at room temperature. The mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate) to give 6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methyl Benzofuran-3-carboxamide (230 mg, 79%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.47 (s, 1 H) 8.12 (s, 1 H) 7.96 (dd, J = 8.98, 5.47 Hz, 2 H) 7.60 (t, J = 2.05 Hz , 1 H) 7.27-7.54 (m, 5 H) 7.18 (s, 1 H) 3.41 (s, 3 H) 2.82 (d, J = 4.69 Hz, 3 H) 2.07-2.22 (m, 1 H) 0.65- 1.09 (m, 3 H) 0.41 (m, 1 H). LCMS (m / z, ES ⁺ ) = 557, 559 (M + H, M + 2).

Step 5: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-vinylphenyl) methylsulfonamido) benzofuran-3-carboxamide
6- (N- (3-bromophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (221 mg, 0.396 mmol), 4,4,5 , 5-Tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.134 mL, 0.793 mmol), [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II), complex with dichloromethane A mixture of (32.4 mg, 0.040 mmol) and sodium carbonate (126 mg, 1.189 mmol) in dioxane: water / 4: 1 (5 mL) was heated in a microwave reactor at 130 ° C. for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through celite. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane: EtOAc) to give 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-vinylphenyl) Methylsulfonamido) benzofuran-3-carboxamide (171 mg, 85% purity) was obtained as a sticky off-white foam. LCMS (m / z, ES ⁺ ) = 505 (M + H ⁺ ). This material was used in the next step without further purification.

Step 6: 5-Cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (2- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) ethyl) phenyl) methylsulfonamido) benzofuran-3-carboxamide bis (1,5-cyclooctadiene) diiridium (I) dichloride (5.29 mg, 7.88 μmol) and diphenylphosphinobutane (6.72 mg 0.016 mmol) was dissolved in THF (2 mL) under nitrogen. 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3-vinylphenyl) methylsulfonamido) benzofuran-3-carboxamide (159 mg, 0.315 mmol) in THF (2 mL) The suspension was added. After stirring for 10 minutes, pinacol borane (1M in THF) (0.95 mL, 0.945 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was subjected to silica gel chromatography (dichloromethane: methanol) to give 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (2- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) phenyl) methylsulfonamido) benzofuran-3-carboxamide (75 mg, 38%, purity 82%) was obtained. This material was used in the next step without further purification. LCMS (m / z, ES ⁺ ) = 633 (M + H ⁺ ).

Step 7: (3- (N- (5-Cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenethyl) boronic acid sodium periodate (380 mg , 1.78 mmol) and 1N aqueous HCl (1.5 mL, 1.5 mmol) were added to 5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (N- (3- (2- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) phenyl) methylsulfonamido) benzofuran-3-carboxamide (75 mg, 0.119 mmol) in THF (3 mL) cold (0 ° C.) Added to the solution. The mixture was stirred at 0 ° C. for 10 minutes and then warmed to room temperature. After 1 hour, the reaction mixture was diluted with EtOAc and the organic layer was separated, washed with 5% aqueous sodium thiosulfate and brine, and dried over sodium sulfate. The solvent was evaporated and the residue was subjected to reverse phase HPLC (C18, acetonitrile: water with 0.1% formic acid) to give the title compound (22 mg, 34%) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) d ppm 8.42-8.53 (m, 1 H) 8.06-8.13 (m, 1 H) 7.92-8.02 (m, 2 H) 7.55 (s, 2 H) 7.34- 7.46 (m, 3 H) 7.24-7.30 (m, 2 H) 7.14-7.18 (m, 1 H) 7.04-7.11 (m, 1 H) 2.83 (d, J = 4.68 Hz, 3 H) 2.58-2.67 ( m, 2 H) 2.48-2.55 (m, 3 H) 2.15-2.31 (m, 1 H) 0.94-1.11 (m, 1 H) 0.75-0.94 (m, 4 H) 0.47 (m, 1 H). LCMS (m / z, ES ⁺ ) = 551 (M + H +).

Example 27: 6- (N- (3-chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) ) -N-Methylbenzofuran-3-carboxamide

Step 1: 6- (N- (3-Chloro-4-vinylphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-chlorophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (1.00 g, 1.69 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (138mg, 0.169mmol), sodium carbonate (537 mg, 5.07 mmol) and vinylboronic acid pinacol ester (0.573mL, 3.38mmol) and 1,4-dioxane and water 9: The mixture in one mixture (20 mL) was degassed and heated at 80 ° C. for 16 hours. The mixture was cooled to room temperature, then poured into water and extracted with EtOAc (3 times). The combined organic layers were washed with brine (1 ×), dried over sodium sulfate, and concentrated under reduced pressure. The pale brown oily residue was purified by flash chromatography (silica gel, 0-50% EtOAc in hexanes gradient) to give the title compound (821 mg, 90%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.46 (q, 1H), 8.08-8.14 (m, 1H), 7.92-8.02 (m, 2H), 7.70-7.76 (m, 1H), 7.34- 7.47 (m, 4H), 7.17-7.24 (m, 1H), 6.96 (dd, 1H), 5.87 (d, 1H), 5.44 (d, 1H), 3.39-3.47 (m, 3H), 2.83 (d, 3H), 2.04-2.16 (m, 1H), 0.73-1.03 (m, 3H), 0.36-0.55 (m, 1H). LCMS (m / z, ES ⁺ ) = 539 (M + H +).

Step 2: 6- (N- (3-Chloro-4-formylphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
1 of 6- (N- (3-chloro-4-vinylphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (890 mg, 1.65 mmol) The suspension in 1 THF / water (36 mL) was treated with a solution of osmium tetroxide (2.5% in t-butanol, 0.415 mL, 0.033 mmol) and stirred for several minutes. The resulting solution was treated with sodium periodate (883 mg, 4.13 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with 1: 1 water / brine (1 ×) and then brine (1 ×). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered, and the filtrate was purified by flash chromatography (silica gel, gradient of 0-50% EtOAc in hexanes) to give the title compound (0.45 g, 50%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.23 (s, 1H), 8.45-8.53 (m, 1H), 8.04 (s, 1H), 7.94-8.01 (m, 2H), 7.86 (d, 1H), 7.35-7.46 (m, 3H), 7.31 (dd, 1H), 7.24-7.29 (m, 1H), 3.57 (s, 3H), 2.84 (d, 3H), 1.89-1.98 (m, 1H) , 0.68-1.02 (m, 3H), 0.42-0.58 (m, 1H). LCMS (m / z, ES ⁺ ) = 541 (M + H +).

Step 3: 6- (N- (3-Chloro-4- (1-hydroxyallyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (3-chloro-4-formylphenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (0.25 g, 0.46 mmol) The solution in THF (10 mL) was cooled to 0 ° C. and treated with vinylmagnesium bromide (1M in THF, 1.02 mL). As the bath melted, the reaction mixture was warmed to room temperature. After 5 hours, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2.times.). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient 0-60% EtOAc in hexanes) afforded the title compound (188 mg, 72%) as a white foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.45 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.36-7.56 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.71 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.04-5.11 (m, 1H), 3.40 (s, 3H), 2.83 (d , 3H), 2.09-2.19 (m, 1H), 0.76-1.07 (m, 3H), 0.39-0.54 (m, 1H). LCMS (m / z, ES ⁺ ) = 569 (M + H +).

Step 4: 6- (N- (3-Chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran- 3-carboxamide
6- (N- (3-chloro-4- (1-hydroxyallyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (210 mg, To a solution of 0.37 mmol) in THF (7 mL) was added DIEA (0.084 mL, 0.48 mmol) and chloromethyl methyl ether (0.16 mL, 2.12 mmol). The reaction mixture was heated at 50 ° C. overnight. Further DIEA (0.32 mL, 1.85 mmol) was added and heating was continued for another 5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2.times.). The combined organic layers were washed with brine (1 ×), dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient from 0 to 60% EtOAc in hexanes) afforded the title compound (175 mg, 77%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.45 (q, 1H), 8.10 (s, 1H), 7.93-8.00 (m, 2H), 7.36-7.53 (m, 5H), 7.19 (s, 1H), 5.88 (ddd, 1H), 5.38 (d, 1H), 5.18-5.30 (m, 2H), 4.66 (d, 1H), 4.53 (d, 1H), 3.38-3.46 (m, 3H), 3.23 (s, 3H), 2.83 (d, 3H), 2.08-2.17 (m, 1H), 0.92-1.06 (m, 1H), 0.75-0.91 (m, 2H), 0.39-0.51 (m, 1H). LCMS (m / z, ES ⁺ ) = 613 (M + H +).

Step 5: 6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-Methylbenzofuran-3-carboxamide
6- (N- (3-Chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide A solution of (125 mg, 0.20 mmol) in THF (10 mL) was treated with Rh (CO) Cl (PPh ₃ ) ₂ (14 mg, 0.02 mmol), purged with nitrogen, and a solution of pinacolborane (1 M in THF, 1.22 mL). After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was dissolved in THF (10 mL) and treated with (Ir (COD) Cl) ₂ (13.7 mg, 0.02 mmol) and DPPE (16.3 mg, 0.041 mmol). After stirring for 5 minutes, a solution of pinacolborane (1M in THF, 1.22 mL) was added. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. Separately, using the same step sequence, 6- (N- (3-chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) The above procedure was repeated with -N-methylbenzofuran-3-carboxamide (49 mg, 0.08 mmol) using a proportional amount of the same reagent. Both of these residues were subjected to purification by flash chromatography (silica gel, gradient from 0 to 100% EtOAc in hexanes) to give a pale yellow oil which was then used without characterization. The oil was dissolved in THF (5 mL) and 1N HCl (5 mL) and heated at 70 ° C. for 16 h, at which point methanol (1 mL) was added and heating was continued for 1 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2.times.). The combined organic layers were washed with brine (1 ×), dried over sodium sulfate, and concentrated under reduced pressure. Purify by flash chromatography (silica gel, gradient 0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) to give the title compound (32 mg, 19% over 2 steps) as an off-white foam. Got as. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.79 (s, 1H), 8.45 (q, 1H), 8.12 (s, 1H), 7.91-8.01 (m, 2H), 7.34-7.54 (m, 5H), 7.18 (s, 1H), 5.32 (t, 1H), 3.38-3.44 (m, 3H), 2.83 (d, 3H), 2.36-2.46 (m, 1H), 2.09-2.21 (m, 1H) , 1.49-1.63 (m, 1H), 0.76-1.09 (m, 5H), 0.35-0.55 (m, 1H). LCMS (m / z, ES ⁺ ) = 597 (M + H +).

Example 28: 6- (N- (3-chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) ) -N-methylbenzofuran-3-carboxamide, enantiomer 1

Step 1: 6- (N- (3-Chloro-4- (1-hydroxyallyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide , Enantiomers 1 and 2
6- (N- (3-chloro-4-formylphenyl) methylsulfonamide) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (1.17 g, 2.16 mmol) The solution in THF (20 mL) was cooled to 0 ° C. and treated with vinylmagnesium bromide (1M in THF, 4.76 mL). As the bath melted, the reaction mixture was warmed to room temperature. After several hours, more vinylmagnesium bromide (0.43 mL) was added. Stirring was continued and the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2x). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient from 0 to 60% EtOAc in hexanes) afforded the title compound (0.87 g, 71%) as a white foam. Enantiomers were separated by supercritical fluid chromatography (Chiral Tech ADH, 30% methanol, 140 bar, 40 ° C., 90 mL / min). All enantiomers were white foams. The earlier eluting enantiomer 1 weighed 380 mg and the later eluting enantiomer 2 weighed 370 mg. Enantiomer # 1 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.44 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.35-7.55 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.70 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt, 1H), 3.40 (s, 3H), 2.83 ( d, 3H), 2.10-2.20 (m, 1H), 0.77-1.06 (m, 3H), 0.40-0.53 (m, 1H). LCMS (m / z, ES ⁺ ) = 569 (M + H +). Enantiomer # 2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.44 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.36-7.56 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.70 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt, 1H), 3.40 (s, 3H), 2.83 ( d, 3H), 2.09-2.20 (m, 1H), 0.76-1.06 (m, 3H), 0.40-0.54 (m, 1H). LCMS (m / z, ES ⁺ ) = 569 (M + H +).

Step 2: 6- (N- (3-Chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran- 3-carboxamide, enantiomer 1
6- (N- (3-chloro-4- (1-hydroxyallyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide, enantiomer 1 To a solution of (350 mg, 0.62 mmol) in THF (10 mL) was added DIEA (0.32 mL, 1.85 mmol) and chloromethyl methyl ether (0.12 mL, 1.54 mmol). The reaction mixture was heated at 50 ° C. overnight. Additional DIEA (0.32 mL, 1.85 mmol) and chloromethyl methyl ether (0.12 mL, 1.54 mmol) were added and heating continued for an additional 24 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2.times.). The combined organic layers were washed with brine (1 ×), dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient from 0 to 50% EtOAc in hexanes) afforded the title compound (350 mg, 93%) as a colorless semi-solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.46 (q, 1H), 8.10 (s, 1H), 7.91-7.99 (m, 2H), 7.35-7.52 (m, 5H), 7.18 (s, 1H), 5.87 (ddd, 1H), 5.36 (d, 1H), 5.17-5.29 (m, 2H), 4.65 (d, 1H), 4.52 (d, 1H), 3.42 (s, 3H), 3.22 (s , 3H), 2.82 (d, 3H), 2.05-2.17 (m, 1H), 0.92-1.04 (m, 1H), 0.73-0.89 (m, 2H), 0.37-0.50 (m, 1H). LCMS (m / z, ES ⁺ ) = 613 (M + H +).

Step 5: 6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide, enantiomer 1
6- (N- (3-Chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide A solution of enantiomer 1 (52 mg, 0.085 mmol) in THF (5 mL) was treated with (Ir (COD) Cl) ₂ (5.7 mg, 8.5 μmol) and DPPE (6.8 mg, 0.017 mmol). After stirring for 25 minutes, a solution of pinacolborane (1M in THF, 0.25 mL) was added. The reaction mixture was stirred for 0.5 h and concentrated under reduced pressure. Separately, 6- (N- (3-chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3 The above procedure was repeated with carboxamide, enantiomer 1 (296 mg, 0.48 mmol) using proportional amounts of reagents. The two residues were subjected to purification by flash chromatography (silica gel, gradient from 0 to 100% EtOAc in hexanes) to give a colorless oil which was then used without characterization. The oil was dissolved in THF (10 mL), 1N HCl (10 mL) and MeOH (1 mL) and heated at 70 ° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2.times.). The combined organic layers were washed with brine (1 ×), dried over sodium sulfate, and concentrated under reduced pressure. Purify by flash chromatography (silica gel, gradient 0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization to give the title compound (85 mg, 25% over 2 steps). Obtained as a fluffy white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.79 (s, 1H), 8.40-8.49 (m, 1H), 8.12 (s, 1H), 7.92-8.03 (m, 2H), 7.34-7.56 ( m, 5H), 7.19 (s, 1H), 5.29-5.37 (m, 1H),
3.38-3.46 (m, 3H), 2.84 (d, 3H), 2.37-2.47 (m, 1H), 2.10-2.22 (m, 1H), 1.50-1.73 (m, 1H), 0.75-1.08 (m, 5H ), 0.37-0.56 (m, 1H). LCMS (m / z, ES ⁺ ) = 597 (M + H +).

Example 29: 6- (N- (3-chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) ) -N-methylbenzofuran-3-carboxamide, enantiomer 2

Step 1: 6- (N- (3-Chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran- 3-carboxamide, enantiomer 2
6- (N- (3-chloro-4- (1-hydroxyallyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide, enantiomer 2 To a solution of (340 mg, 0.58 mmol) in THF (7 mL) was added DIEA (0.42 mL, 2.39 mmol) and chloromethyl methyl ether (0.14 mL, 1.79 mmol). The reaction mixture was heated at 50 ° C. overnight. Additional DIEA (0.42 mL, 2.39 mmol) and chloromethyl methyl ether (0.14 mL, 1.79 mmol) were added and heating continued for an additional 24 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2.times.). The combined organic layers were washed with brine (1 ×), dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient from 0 to 50% EtOAc in hexanes) gave the title compound (342 mg, 93%) as a colorless semi-solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.45-8.51 (m, 1H), 8.12 (s, 1H), 7.94-8.02 (m, 2H), 7.37-7.54 (m, 5H), 7.20 ( s, 1H), 5.89 (ddd, 1H), 5.38 (d, 1H), 5.18-5.32 (m, 2H), 4.67 (d, 1H), 4.54 (d, 1H), 3.44 (s, 3H), 3.24 (s, 3H), 2.84 (d, 3H), 2.08-2.19 (m, 1H), 0.77-1.06 (m, 3H), 0.41-0.51 (m, 1H). LCMS (m / z, ES ⁺ ) = 613 (M + H +).

Step 2: 6- (N- (3-Chloro-4- (2-hydroxy-1,2-oxaborolan-5-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide, enantiomer 2
6- (N- (3-Chloro-4- (1- (methoxymethoxy) allyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide A solution of enantiomer 2 (340 mg, 0.56 mmol) in THF (15 mL) was treated with (Ir (COD) Cl) ₂ (37 mg, 0.055 mmol) and DPPE (44 mg, 0.11 mmol). After stirring for 30 minutes, a solution of pinacolborane (1M in THF, 1.66 mL) was added. The reaction mixture was stirred for 0.5 h and concentrated under reduced pressure. The residue was subjected to purification by flash chromatography (silica gel, gradient from 0 to 100% EtOAc in hexanes) to give a colorless oil which was then used without characterization. The oil was dissolved in THF (10 mL), 1N HCl (10 mL) and MeOH (1 mL) and heated at 70 ° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2.times.). The combined organic layers were washed with brine (1 ×), dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient 0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization gave the title compound (124 mg, 38% over 2 steps). Obtained as a fluffy white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.79 (s, 1H), 8.42-8.49 (m, 1H), 8.12 (s, 1H), 7.93-8.02 (m, 2H), 7.35-7.55 ( m, 5H), 7.19 (s, 1H), 5.33 (t, 1H), 3.39-3.45 (m, 3H), 2.84 (d, 3H), 2.37-2.47 (m, 1H), 2.12-2.22 (m, 1H), 1.49-1.64 (m, 1H), 0.77-1.07 (m, 5H), 0.41-0.52 (m, 1H). LCMS (m / z, ES ⁺ ) = 597 (M + H +).

Example 30: 5-Cyclopropyl-2- (4-fluorophenyl) -6- (N- (1-hydroxy-3,4-dihydro-1H-benzo [c] [1,2] oxaborin-6-yl ) Methylsulfonamide) -N-methylbenzofuran-3-carboxamide

Step 1: Dimethyl 2- (5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrophenyl) malonate
To a stirred suspension of Cs ₂ CO ₃ (17.5 g, 53.8 mmol) in DMF (20 ml) was added dimethyl malonate (2.57 mL, 22.4 mmol) at room temperature under a nitrogen atmosphere. This was followed by 6- (N- (3-chloro-4-nitrophenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (10.0 g, 17.9 mmol) sonicated solution in DMF (50 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 x 40 mL). The organic layer was washed with water (3 x 50 mL), dried over sodium sulfate and evaporated to dryness. The crude product was triturated with ether and the solid was collected by filtration to give the title compound in 68% yield. ¹ H NMR (400 MHz, DMSO-d 6) δ ppm 8.51 (d, J = 4.7 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 8.04 (s, 1H), 7.90-8.00 (m , 2H), 7.36-7.51 (m, 3H), 7.26-7.31 (m, 1H), 7.14-7.20 (m, 1H), 5.45-5.56 (m, 1H), 3.52-3.64 (m, 9H), 2.84 (d, J = 4.5 Hz, 3H), 1.88-2.03 (m, 1H), 0.82-1.00 (m, 2H), 0.69 (d, J = 3.1 Hz, 1H), 0.29-0.50 (m, 1H). LCMS (m / z, ES ⁺ ) = 654 (M + H +).

Step 2: Dimethyl 2- (5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrophenyl) acetic acid 2- (5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrophenyl) malonate (10.0 g, To a stirred solution of 15.1 mmol) 1: 1: 1 THF / MeOH / water was added 3N aqueous NaOH (20 mL). The resulting mixture was heated at 55 ° C. for 15 hours. The reaction mixture was cooled to room temperature and treated with 5N aqueous HCl to pH 5. The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was triturated with methanol and ether and the solid was collected by filtration to give the title compound in 75% yield. ¹ H NMR (400 MHz, DMSO-d 6) δ ppm 12.52 (br. S., 1 H) 8.49 (q, J = 4.23 Hz, 1 H) 8.09-8.15 (m, 1 H) 8.02 (s, 1 H) 7.96 (d, J = 3.32 Hz, 4 H) 7.31-7.44 (m, 4 H) 7.25 (s, 1 H) 3.98 (s, 2 H) 3.56 (s, 3 H) 2.84 (d, J = 4.69 Hz, 3 H) 1.94-2.03 (m, 1 H) 0.85 (d, J = 3.13 Hz, 3 H) 0.48 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 583 (M + H +).

Step 3: Methyl 2- (5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrophenyl) acetate
2- (5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrophenyl) acetic acid (2.00 g, To a stirred solution of 3.44 mmol) in 1: 1 DMF / MeOH (10 mL) was added 2M TMS-diazomethane in hexane (0.786 g, 6.88 mmol) at 0 ° C. and the reaction mixture was stirred for 2 h. The reaction was diluted with water and extracted into EtOAc. The ethyl acetate solution was washed with water, dried over sodium sulfate and evaporated to dryness to give the title compound in 70% yield. ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.04 (d, J = 9.19 Hz, 1 H) 7.88 (br. S., 0 H) 7.80 (t, J = 6.06 Hz, 2 H) 7.46 (s , 1 H) 7.44 (br. S., 1 H) 7.28 (dd, J = 9.18, 1.95 Hz, 1 H) 7.08-7.18 (m, 3 H) 6.13 (br. S., 1 H) 3.88 (s , 2 H) 3.62 (s, 3 H) 3.29 (s, 3 H) 2.93 (d, J = 2.93 Hz, 3 H) 2.88 (s, 2 H) 2.79 (d, J = 1.76 Hz, 1 H) 1.82 -1.93 (m, 1 H) 0.67-0.98 (m, 3 H) 0.49 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 596 (M + H +).

Step 4: methyl 2- (2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) acetate Methyl 2- (5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methyl-carbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrophenyl) acetate (1.00 g, 1.68 mmol) in THF (10 mL) was subjected to atmospheric pressure hydrogenation in the presence of 20% palladium on charcoal. After 10 hours, the reaction vessel was purged with nitrogen, the catalyst was removed by filtration through celite, and the filtrate was concentrated to dryness under reduced pressure. The crude product was subjected to flash chromatography (silica gel, hexane / EtOAc) to give the title compound in 65% yield. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.84-7.92 (m, 2 H) 7.68 (s, 1 H) 7.39 (s, 1 H) 7.23-7.30 (m, 3 H) 7.18 (t, J = 8.60 Hz, 2 H) 6.66 (d, J = 8.40 Hz, 1 H) 5.84 (d, J = 4.49 Hz, 1 H) 4.11-4.19 (m, 2 H) 3.68 (s, 3H) 3.52 (s, 2 H) 3.14-3.20 (m, 3 H) 2.94-3.02 (m, 3 H) 2.21-2.30 (m, 1 H) 0.96 (br. S., 2 H). LCMS (m / z, ES ⁺ ) = 566 (M + H +).

Step 5: 6- (N- (4-amino-3- (2-hydroxyethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide Methyl 2- (2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) phenyl) acetate (500 mg, To a solution of 0.884 mmol) in THF (6 mL) was added 3.5 M lithium aluminum hydride / THF (0.20 mL, 0.71 mmol) at 0 ° C. After stirring at 0 ° C. for 45 min, aqueous workup was followed by flash chromatography (silica gel, hexane / EtOAc) to give the title compound in 65% yield. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.89 (dd, J = 7.82, 5.47 Hz, 1 H) 7.70 (s, 0 H) 7.40 (s, 1 H) 7.15-7.25 (m, 2 H) 6.61-6.73 (m, 1 H) 5.78 (br. S., 0 H) 3.89 (t, J = 5.96 Hz, 1 H) 3.18 (s, 2 H) 3.10-3.24 (m, 3 H) 3.00 (d , J = 4.89 Hz, 1 H) 2.76 (t, J = 5.86 Hz, 1 H) 2.29 (br. S., 0 H) 0.99 (br. S., 2 H). LCMS (m / z, ES ⁺ ) = 538 (M + H +).

Step 6: 6- (N- (4-Bromo-3- (2-hydroxyethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-amino-3- (2-hydroxyethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3 maintained at 0 ° C. To a solution of carboxamide (250 mg, 0.465 mmol) in MeCN (1 mL) was added sodium nitrite (80 mg, 1.16 mmol) dissolved in water (0.50 mL), followed by 48% aqueous HBr (0.25 mL). The resulting mixture was treated with copper (I) bromide (133 mg, 0.930 mmol) in 48% aqueous HBr (0.30 mL). After stirring at 60 ° C. for 1 hour, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic solution was washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / EtOAc) to give the title compound in 65% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.36-8.51 (m, 1 H) 8.05 (s, 1 H) 7.92 (dd, J = 8.89, 5.37 Hz, 2 H) 7.49-7.62 (m, 1 H) 7.31-7.49 (m, 3 H) 7.09-7.26 (m, 2 H) 4.69 (t, J = 5.28 Hz, 1 H) 3.46-3.60 (m, 2 H) 3.30-3.40 (m, 3 H ) 2.72-2.87 (m, 5 H) 2.04-2.22 (m, 1 H) 0.70-1.06 (m, 3 H) 0.41 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 601,603 (M + H +).

Step 7: 5-Cyclopropyl-2- (4-fluorophenyl) -6- (N- (1-hydroxy-3,4-dihydro-1H-benzo [c] [1,2] oxaborin-6-yl) Methylsulfonamide) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3- (2-hydroxyethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (100 mg, 0.166 mmol) of deoxygenated solution in 1,4-dioxane (4 mL) and water (1.0 mL) under nitrogen purge with K ₂ CO ₃ (92 mg, 0.665 mmol) followed by 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (84 mg, 0.33 mmol) and PdCl ₂ (dppf) (12.16 mg, 0.017 mmol) added. The reaction mixture was then heated to 70 ° C. for 2 hours. The mixture was cooled to room temperature and filtered to remove solids. The filtrate was diluted with water and extracted with EtOAc. The EtOAc solution was washed with water (1 ×), dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by RP-HPLC (C18, MeCN / water / 0.1% formic acid) to give the title compound in 65% yield. ¹ H NMR (400 MHz, DMSO-d 6) δ ppm 7.89 (dd, J = 8.60, 5.28 Hz, 2 H) 7.67-7.71 (m, 1 H) 7.57-7.62 (m, 1 H) 7.45-7.49 ( m, 1 H) 7.13-7.25 (m, 4 H) 5.79 (d, J = 3.91 Hz, 1 H) 4.31 (s, 1 H) 4.19 (t, J = 5.96 Hz, 2 H) 3.29 (s, 3 H) 3.01 (d, J = 4.89 Hz, 3 H) 2.89 (t, J = 5.86 Hz, 2 H) 2.02-2.13 (m, 1 H) 1.02 (br. S., 1 H) 0.83 (br. S ., 2 H) 0.61 (br. S., 1 H). LCMS (m / z, ES ⁺ ) = 549 (M + H +).

Example 31: 6- (N- (7-chloro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamido) -5-cyclopropyl-2- (4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide

Step 1: methyl 5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrobenzoate
5-cyclopropyl-2- (4-fluorophenyl) -N-methyl-6- (methylsulfonamido) benzofuran-3-carboxamide (55.0 g, 123 mmol), methyl 5-fluoro-2-nitrobenzoate (36.7 g, 184 mmol), and sodium carbonate (39.1 g, 369 mmol) in DMF (400 mL) was heated to 70 ° C. with vigorous stirring. After 72 hours, LCMS showed that the reaction was almost complete. The mixture was cooled to room temperature, diluted with EtOAc (300 mL) and filtered through a bed of celite to remove solids. The filter cake was washed with EtOAc until the filtrate was colorless to give a total filtrate volume of 1.2 L. The filtrate was transferred to a separatory funnel and partitioned with 5% aqueous NaCl (1.4 L) and the phases separated. The aqueous solution was further extracted twice with EtOAc (300 mL). The combined EtOAc solution was washed with 95% aqueous NaCl (2 ×), saturated aqueous NaCl (1 ×), dried over sodium sulfate, and concentrated to about 200 mL by rotary evaporation. At this point the solid began to crystallize. The suspension was diluted with DCM (200 mL) and the suspension was stirred overnight. The suspension was then cooled in an ice-water bath for 2 hours and the solid was collected by vacuum filtration. The filter cake was washed twice with chilled 1: 1 EtOAc / DCM, suction dried for 30 minutes, then dried in vacuo overnight and methyl 5- (N- (5-cyclopropyl-2- (4-fluorophenyl) ) -3- (Methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrobenzoate (59.6 g, 83%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.52 (q, J = 4.42 Hz, 1 H) 8.13 (d, J = 9.07 Hz, 1 H) 8.08 (s, 1 H) 7.93-8.01 (m , 2 H) 7.57 (d, J = 2.63 Hz, 1 H) 7.53 (dd, J = 9.07, 2.73 Hz, 1 H) 7.38-7.46 (m, 2 H) 7.29 (s, 1 H) 3.83 (s, 3 H) 3.60 (s, 3 H) 2.85 (d, J = 4.59 Hz, 3 H) 1.87-2.04 (m, 1 H) 0.87 (m, 2 H) 0.73 (m, 1 H) 0.46 (m, 1 H). LCMS (ESI): 582 (M + H +).

Step 2: methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate methyl 5- (N -(5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) -2-nitrobenzoate (59.5 g, 102 mmol) and 10% Pd (C) A stirred suspension of (6.0 g) in 2: 1 THF / EtOH (1.2 L) was saturated with hydrogen by bubbling hydrogen gas for 10 minutes and then subjected to balloon hydrogenation at room temperature. After 6 hours, LCMS showed that the reaction was complete. After 24 hours, the mixture was purged with nitrogen, the catalyst was removed by filtration through celite, and the filtrate was concentrated to dryness under reduced pressure to give a pale yellow solid. This material was recrystallized from hot EtOAc to give methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfone. Amide) benzoate (42.2 g) was obtained as a white solid. The filtrate was concentrated to dryness under reduced pressure and further methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfone. Amido) benzoate (13.0 g) was obtained as a pale yellow foam which was determined to be 95% pure by LCMS. The sum of the two batches is the sum of methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate The yield was 55.2 g (98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.46 (q, J = 4.42 Hz, 1 H) 8.16 (s, 1 H) 7.91-8.00 (m, 3 H) 7.61 (dd, J = 8.98, 2.73 Hz, 1 H) 7.41 (t, J = 8.88 Hz, 2 H) 7.15 (s, 1 H) 6.76-6.86 (m, 3 H) 3.79 (s, 3 H) 3.28 (s, 3 H) 2.83 ( d, J = 4.68 Hz, 3 H) 2.25-2.38 (m, 1 H) 0.82-1.10 (m, 3 H) 0.42 (m, 1 H). LCMS (ESI): 552 (M + H +).

Step 3: Methyl 2-amino-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate methyl 2-amino-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate (55.0 g, 100 mmol) in DMF ( The suspension in 320 mL) was heated to 60 ° C. The resulting yellow solution was treated with NCS (14.0 g, 105 mmol) in one portion. The solution immediately darkened. After 5 minutes, LCMS showed complete conversion to the desired chloro compound. The solution was cooled to room temperature and diluted with EtOAc (1 L). The resulting solution was 5% NaCl aqueous solution (1 × 1 L), 5% sodium hydrogen sulfite aqueous solution (2 × 200 mL), saturated sodium bicarbonate aqueous solution (3 × 200 mL), and saturated brine aqueous solution (1 × 200 mL). ). The solution is dried over sodium sulfate and concentrated to dryness under reduced pressure to give methyl 2-amino-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) ) Benzofuran-6-yl) methylsulfonamido) benzoate (58.0 g, 99%) was obtained as a brown solid. This material was used in the next step without purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.46 (q, J = 4.42 Hz, 1 H) 8.25 (s, 1 H) 7.94-8.04 (m, 3 H) 7.90 (d, J = 2.63 Hz , 1 H) 7.34-7.46 (m, 2 H) 7.18 (s, 1 H) 6.93 (br. S., 2 H) 3.83 (s, 3 H) 3.33 (s, 3 H) 2.84 (d, J = 4.59 Hz, 3 H) 2.26-2.36 (m, 1 H) 0.84-1.11 (m, 3 H) 0.40 (br. S., 1 H). LCMS (ESI): 586 (M + H +).

Step 4: Methyl 2-bromo-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate Magnetic To a 1 L three-necked flask equipped with a stirrer was added methyl 2-amino-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran- 6-yl) methylsulfonamido) benzoate (58.0 g, 99.0 mmol) was added followed by MeCN (500 mL) followed by 48% aqueous HBr (500 mL). The dark brown solution was cooled to 0 ° C. in an ice water / brine bath and treated with a solution of sodium nitrite (8.20 g, 119 mmol) in water (50 mL) over 5 min. After 30 minutes, LCMS showed that the starting material was completely consumed. The solution was treated with CuBr (18.5 g, 129 mmol) over 2 minutes and then warmed to 50 ° C. After 30 minutes at 50 ° C., LCMS showed that the reaction was complete. The solution was cooled to room temperature and partitioned between EtOAc (1 L) and water (1.5 L). The phases were separated and the aqueous solution was extracted with EtOAc (2 x 200 mL). The combined EtOAc solution was 5% NaCl aqueous solution (1 × 1 L), 5% sodium hydrogen sulfite aqueous solution (2 × 300 mL), saturated sodium bicarbonate aqueous solution (2 × 300 mL), saturated brine aqueous solution (1 × 300 mL). And dried over sodium sulfate. The desiccant was removed by filtration through a pad of silica gel and the filtrate was concentrated to dryness under reduced pressure to give crude methyl 2-bromo-3-chloro-5- (N- (5-cyclopropyl-2- (4 -Fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate (64.3 g) was obtained as a reddish brown foam. The crude product was then used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.50 (q, J = 4.29 Hz, 1 H) 8.16 (s, 1 H) 7.92-8.03 (m, 2 H) 7.79 (d, J = 2.73 Hz , 1 H) 7.65 (d, J = 2.73 Hz, 1 H) 7.41 (t, J = 8.93 Hz, 2 H) 7.24 (s, 1 H) 3.81-3.89 (m, 3 H) 3.45-3.53 (m, 3 H) 2.85 (d, J = 4.59 Hz, 3 H) 2.04-2.16 (m, 1 H) 0.71-1.07 (m, 3 H) 0.40 (br. S., 1 H). LCMS (ESI): 649 (M + H +).

Step 5: 6- (N- (4-Bromo-3-chloro-5- (hydroxymethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3 -Carboxamide Crude methyl 2-bromo-3-chloro-5- (N- (5-cyclopropyl-2- (4-fluorophenyl) -3- (methylcarbamoyl) benzofuran-6-yl) methylsulfonamido) benzoate A solution of (54.3 g, 84.0 mmol) in anhydrous THF (351 mL) and anhydrous MeOH (39 mL) was cooled to −5 ° C. (internal temperature) in an ice water / brine bath. To the stirring solution was added 2M LiBH ₄ / THF (125 mL, 251 mmol) via a dropping funnel at such a rate as to maintain the temperature below 5 ° C. Addition required 35 minutes. The brine bath was then replaced with an ice water bath and stirring of the solution continued. After an additional 1.5 hours, LCMS showed that the reaction was complete. The solution was quenched by adding saturated aqueous sodium bicarbonate (200 mL) followed by water (400 mL) and EtOAc (600 mL). The mixture was stirred vigorously for 30 minutes and then transferred to a separatory funnel. After separation of the phases, the solid remained in the aqueous phase, so more water (200 mL) was added, the mixture was shaken and the phases were separated again. The aqueous solution was extracted with EtOAc (2 x 200 mL). The combined EtOAc solution was washed with 5% aqueous NaCl (1 ×), saturated brine (1 ×), dried over sodium sulfate, concentrated to dryness under reduced pressure, and 6- (N- (4-bromo-3- Chloro-5- (hydroxymethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (54.5 g) as an orange-brown foam It was. The crude was used in the next step without purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.45-8.54 (m, 1 H) 8.12 (s, 1 H) 7.98 (dd, J = 8.93, 5.41 Hz, 2 H) 7.59 (d, J = 2.73 Hz, 1 H) 7.54 (d, J = 2.63 Hz, 1 H) 7.41 (t, J = 8.88 Hz, 2 H) 7.22 (s, 1 H) 5.64 (t, J = 5.56 Hz, 1 H) 4.48 (d, J = 5.56 Hz, 2 H) 3.45 (s, 3 H) 2.84 (d, J = 4.59 Hz, 3 H) 2.06-2.17 (m, 1 H) 0.75-1.06 (m, 3 H) 0.47 ( br. s., 1 H). LCMS (ESI): 623 (M + H +).

Step 6: 6- (N- (4-Bromo-3-chloro-5-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methyl Benzofuran-3-carboxamide Crude 6- (N- (4-Bromo-3-chloro-5- (hydroxymethyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N- A solution of methylbenzofuran-3-carboxamide (50.0 g, 80.0 mmol) in THF (500 mL) was treated with DIEA (42.1 mL, 241 mmol) followed by MOM-Cl (15.3 mL, 201 mmol) and the resulting solution Was heated to 50 ° C. with stirring. After 18 hours, LCMS showed that the reaction was complete. The solution was cooled to room temperature and diluted with EtOAc (600 mL) followed by water (600 mL). After stirring vigorously for 10 minutes, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was further extracted once with EtOAc (200 mL). The combined EtOAc solution was washed with an aqueous solution of 5% citric acid and 5% NaCl (3 x 300 mL), saturated aqueous sodium bicarbonate (2 x 300 mL), saturated brine (1 x 300 mL) and washed with sodium sulfate. Dried. The desiccant was filtered off and the filtrate was concentrated to dryness under reduced pressure to give an orange-brown foam. This material was dissolved in EtOAc (250 mL) and the solution was heated to reflux with stirring. To the solution, hexane (375 mL) was added over 5 minutes while maintaining the reflux temperature. The solution was then cooled to room temperature with stirring, during which time a light tan solid crystallized. After 2 hours, the solution was cooled in an ice-water bath and stirred for an additional 2 hours. The solid was filtered off in a medium fritted funnel. The filter cake was washed with chilled 3: 2 hexane / EtOAc (250 mL), dried by suction filtration for 30 minutes and then dried in vacuo to give 6- (N- (4-bromo-3-chloro-5- ((Methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (36.4 g) was obtained as a light tan solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.49 (q, J = 4.30 Hz, 1 H) 8.14 (s, 1 H) 7.93-8.00 (m, 2 H) 7.62 (d, J = 2.74 Hz , 1 H) 7.52 (d, J = 2.74 Hz, 1 H) 7.40 (t, J = 8.94 Hz, 2 H) 7.21 (s, 1 H) 4.68 (s, 2 H) 4.57 (s, 2 H) 3.44 (s, 3 H) 3.24 (s, 3 H) 2.83 (d, J = 4.59 Hz, 3 H) 2.06-2.19 (m, 1 H) 0.74-1.05 (m, 3 H) 0.44 (br. s., 1 H).

Step 7: 6- (N- (7-chloro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methylsulfonamido) -5-cyclopropyl-2- ( 4-Fluorophenyl) -N-methylbenzofuran-3-carboxamide
6- (N- (4-Bromo-3-chloro-5-((methoxymethoxy) methyl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3 - carboxamide (46.4 g, 69.7 mmol), bis (pinacolato) diboron (44.2 g, 174 mmol), potassium acetate (27.4 g, 279 mmol), and _{Pd (dppb) Cl 2 (2.10g} , 3.48mmol) in 1,4 The mixture in dioxane (350 mL) was sparged with nitrogen for 15 minutes and then heated to 108 ° C. under nitrogen. After 22 hours, LCMS showed complete conversion of the starting material to an 84:16 mixture of the desired product / prothio byproduct (bromine replaced with hydrogen). The mixture was cooled to room temperature, combined with the crude reaction mixture from the 1 g scale pilot reaction and diluted with EtOAc (500 mL). The mixture was filtered through a pad of silica gel to remove solids and the filtrate was concentrated under reduced pressure to give 6- (N- (3-chloro-5-((methoxymethoxy) methyl) -4- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (93.1 g ) Was obtained as a light tan solid. LCMS (ESI): 713 (M + H ^< + ^> ). This material was dissolved in 5: 1 THF / MeOH (524 mL) and the solution was treated with 1N aqueous HCl (440 mL). A tan solid quickly precipitated. The mixture was heated to 70 ° C. The solid slowly dissolved to give a yellow solution. After 18 hours, LCMS showed that the reaction was complete. The solution was cooled to about 40 ° C. and poured into a rapidly stirred mixture of water (1 L) and MTBE (1 L). To the mixture was added 1N aqueous NaOH (440 mL). The pH was then adjusted to about 12-13 by adding 3N aqueous NaOH. The mixture was transferred to a separatory funnel and the phases were separated. Two phase analysis by TLC and LCMS showed almost complete separation of the desired product from the prothio byproduct. The aqueous phase was washed with MTBE (3 x 250 mL) and then treated with concentrated HCl to a pH of about 2. The resulting cloudy solution was extracted with EtOAc (4 x 500 mL). The combined EtOAc extracts were washed with 5% brine aqueous solution (1 ×), saturated brine aqueous solution (1 ×) and dried over sodium sulfate. The desiccant was removed by filtration through a pad of celite to give a pale yellow filtrate. The filtrate was concentrated to dryness under reduced pressure to give a tan foam (39.0 g). This material was dissolved in MeCN (400 mL). While stirring the resulting solution, 0.1 N HCl aqueous solution (800 mL) was slowly added over 40 minutes with a dropping funnel. At the beginning of the addition, a small amount of previously prepared crystalline 6- (N- (7-chloro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) methyl Seeding sulfonamide) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide into the solution induced vigorous crystallization. The suspension was stirred overnight at room temperature. The solid was collected by vacuum filtration and rinsed with 2: 1 MeCN water. This material is air-dried for 1 hour and then dried in vacuo to constant weight to give 6- (N- (7-chloro-1-hydroxy-1,3-dihydrobenzo [c] [1,2] Oxabolol-5-yl) methylsulfonamido) -5-cyclopropyl-2- (4-fluorophenyl) -N-methylbenzofuran-3-carboxamide (28.8 g, 71%) was obtained as an off-white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.18 (s, 1 H) 8.50 (q, J = 4.42 Hz, 1 H) 8.09 (s, 1 H) 7.93-8.02 (m, 2 H) 7.37 -7.46 (m, 3 H) 7.28 (d, J = 1.56 Hz, 1 H) 7.22 (s, 1 H) 4.97 (s, 2 H) 3.48 (s, 3 H) 2.85 (d, J = 4.59 Hz, 3 H) 2.02-2.14 (m, 1 H) 0.92-1.04 (m, 1 H) 0.82 (br. S., 2 H) 0.49 (br. S., 1 H). LCMS (ESI): 569 (M + H +).

Example 32: Assay method based on biologically active replicon luciferase cells A 1 mM stock solution (150 μL) of each test compound in DMSO is transferred to the first row of a 96-well V-bottom microplate and the maximum concentration of the required dilution series is 200. Got double. A 50 μL aliquot was added to each well in the remaining row containing DMSO (100 μL) to obtain a 1: 3 dilution series over 10 points. Columns 11 and 12 contained DMSO only for positive and negative controls, respectively. Add 10 μL of each well to DMEM medium (Invitrogen # 41965- supplemented with 5% v / v fetal bovine serum, 1% v / v non-essential amino acid solution, 100 units / ml penicillin, 100 μg / ml streptomycin and 2 mM L-glutamine. 039) (90 μL) to obtain 20 times the maximum concentration of the required dilution series.

Genotype 1b linked to a firefly luciferase reporter gene (Pietschmann, T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. and Bartenschlager, R., Journal of Virology, 2002, 76, 4008-4021), genotype 1a (Blight, KJ, McKeating, JA, Marcotrigiano, J., and Rice, CM of Journal of Virology, 2003, 77, 3180-3190, subline 1.19 constructed in-house from H77 SG-Neo containing the adaptive mutations P1496L and S2204I), genotype 1b C316N (site-specific mutation of NS5B gene of ET subline) Adaptive mutation described by Genotype 1a C316Y (Blight, KJ, McKeating, JA, Marcotrigiano, J., and Rice, CM, Journal of Virology, 2003, 77, 3180-3190) In-house by site-directed mutagenesis of NS77B gene of H77 SG-Neo including P1496L and S2204I) with any subgenomic HCV NS3-NS5B replicon The suspension was prepared from a culture of transfected Huh-7 cells to a constant. The nearly confluent monolayer was peeled from the growth flask with Versen-trypsin solution, and the cells were resuspended in assay medium containing DMEM. A 95 μL suspension containing 15,000 cells (genotype 1b luciferase replicon) or 20,000 cells (genotype 1a luciferase replicon) was added to all wells of the 96 well plate (Perkin Elmer, # 6005686) Added to the control). 5 μL of the compound solution was added to the cell suspension and the plate was incubated for 48 hours at 37 ° C. in a 5% CO ₂ atmosphere.

  For toxicity, cells in one plate were treated with Cell Titer Glo (Promega, # G7573). Cell Titer Glo solution was prepared according to the manufacturer's instructions and 100 μL was added to each well. The plate emission was then read on Envision. For efficacy, Steady Glo (Promega, # E2550) solution was prepared according to the manufacturer's instructions and added to each well at 100 μL. After incubation for 20 minutes, the luminescence of the plate was read on Envision.

Data analysis Toxicity: Luminescence values from replicate wells were averaged and expressed as a percentage of the average absorbance of control wells without compound to determine comparative cell viability. Compound cytotoxicity is expressed as the lowest concentration at which a significant decrease in viability is observed, or the percentage cytotoxicity relative to compound concentration using ActivityBase (IDBS) software and curve fitting performed through the XC50 module. The 50% toxic concentration (CCID ₅₀ ) was determined by plotting.

Efficacy: luminescence values from all cell-containing wells without compound were averaged to obtain a positive control value. Mean luminescence values from wells without compounds to which no cells were added were used to provide negative (background) control values. The readings obtained from the wells at each compound concentration were averaged and expressed as a percentage of the positive control signal after subtracting the average background value from all measurements. A decrease in the quantifiable and specific luciferase signal in the presence of the drug is a direct measure of replicon inhibition. Using BioAssay Enterprise (CamebridgeSoft) and the XC50 module for curve fitting, a curve of percentage inhibition against compound concentration was plotted to derive a 50% inhibitory concentration (IC ₅₀ ) for the compound. EC ₅₀ is the effective concentration, ie the concentration of compound at which 50% of the maximum effect is observed. The EC ₅₀ values of two identical plates were averaged. The results are shown in Table 1 as EC ₅₀ for genotype (GT) 1a, 1b, 1b 316N and 1a 316Y.

Example 33: Pharmacokinetics In vivo pharmacokinetic studies were performed in mice, rats, dogs, or cynomolgus monkeys to determine clearance, oral exposure, and bioavailability (% F). Solution doses of compounds were administered intravenously through catheters or orally by gavage. Blood samples were collected at the following time points (n = 2 or 3 / route / species): 0.083 (intravenous (IV) only), 0.167 (intravenous (IV) only), 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. Non-compartment pharmacokinetic parameters were determined using Phoenix Winnonlin 6.1 (Pharsight, Mountain View, CA). The bioavailability of the oral formulation of each compound was calculated as the ratio of oral dose normalized AUC _inf to intravenous dose normalized AUC _inf . The results are shown in Table 2.

Example 34: Human hepatocytes
Hepatocyte incubation was performed using cryopreserved hepatocytes purchased from CellzDirect (Durham, NC). Cryopreserved hepatocytes were removed from liquid nitrogen and thawed using a hepatocyte isolation kit K2000 (12/13/2004) according to XenoTech guidelines described in “XenoTech Protocol for Thawing Cryopreserved Hepatocytes”. Hepatocytes were diluted to 1 × 10 ⁶ cells in Williams E medium (1 mL) containing 25 mM HEPES buffer and 2 mM Glutamax.

Hepatocyte incubation was performed in 96-well plates on an Eppendorf shaker at 37 ° C and 350 rpm. The reaction mixture consisted of 0.25 × 10 ⁶ cells and 0.5 mM test compound (to maintain a final DMSO concentration of 0.05%) in a final volume (0.5 mL). Collected at an initial time point (t ₀ ) and later aliquots at 15, 30, 60, 90, and 120 minutes. The reaction was terminated by transferring 50 mL of the incubation mixture at 4 ° C. to a 96 well plate containing 100 mL of organic mixture [acetonitrile and methanol (80:20)]. Precipitated protein was removed by centrifugation, and the resulting supernatant was transferred to a new 96-well polypropylene plate for LC / MS / MS analysis. In each experiment, drug-free matrix controls and 2QC standards (phenacetin and propranolol) were incubated and treated similarly to the test compounds.

Metabolic stability, expressed as the percentage of parent compound remaining, is calculated from the ratio of the compound peak area remaining after incubation (t _x ) to the compound peak area at time zero incubation (t ₀ ). did.

The half-life (t _1/2 ) was calculated using the following equation:

  In the formula, K is the slope of ln (%) of the remaining compound with respect to time regression. Half-life values are reported only when a decrease of at least 15% of the parent compound is observed.

Specific clearance is determined from the microsomal liver cells incubated (Cl _'int, mL / min / kg body weight) was calculated from the half-life value using following equations (Obach, Obach, RS J. Pharmacol . Expt Ther , 283: 46-58, 1997):

Where B = g (liver) / kg (body weight) (Davies and Morris, 1993), C = # cells / g (liver) (Iwatsubo, Pharmacol. Ther., 73: 147-171, 1997)
B = 1.2 x 10 ⁸ cells / g (mouse, rat, cynomolgus monkey and human) or 2.4 x 10 ⁸ cells / g (dog)
C = 87.5 gm (liver) / kg (body weight) (mouse), 40 gm (liver) / kg (body weight) (rat), 32 gm (liver) / kg (body weight) (dog), 20 gm (liver) / kg (body weight) (cynomolgus monkey), 26 gm (liver) / kg (body weight) (human).

If the half-life value was determined to be greater than 3 times the final time point (ie t _1/2 > 360 minutes in hepatocytes), no Cl ′ _int value was reported.

Results: T _1/2 (min) for Example 1 was>360;A>360; B = 45; C (not measured); D = 61.6; Example 15> 360.

Claims (1)

The following structure:

A method for producing a compound represented by the following steps:
(1) The following structure:

Is reacted with p-benzoquinone in the presence of anhydrous ZnCl ₂ in methanol under N ₂ to give the following structure:

Producing a compound represented by:
(2) The product compound of step (1) is reacted with isopropyl bromide under N _{2 in} the presence of CsCO _{3 in} N-methyl-2-pyrrolidone to give the following structure:

Producing a compound represented by:
(3) The product of step (2) is reacted with nitric acid in CHCl ₃ to form the following structure:

Producing a compound represented by:
(4) The product compound of step (3) is reacted with BCl _{3 in} CH ₂ Cl ₂ under N ₂ to give the following structure:

Producing a compound represented by:
(5) The product compound of step (4), N ₂ under, CH ₂ Cl ₂ of 4 (dimethylamino) pyridine and triethylamine and trifluoromethanesulfonic anhydride (CF ₃ SO ₂₎ reaction in the presence of ₂ O Let the following structure:

Producing a compound represented by:
(6) The product compound of step (5) is reacted with cyclopropylboronic acid, KF and NaBr in the presence of Pd (PPh ₃ ) ₄ and has the following structure:

Producing a compound represented by:
(7) The product compound of step (6) is reduced in 2M HCl in ethyl acetate in the presence of 10% Pd / C and hydrogen gas to give the following structure:

Producing a compound represented by:
(8) The product of step (7) is reacted with CH ₃ SO ₂ Cl in the presence of triethylamine in CH ₂ Cl _{2 to} give the following structure:

Producing a compound represented by:
(9) The product compound of step (8) is hydrolyzed in ethanol / H ₂ O in the presence of KOH to give the following structure:

Producing a compound represented by:
(10) The product compound of step (9) is triethylamine and 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3 in CH ₂ Cl ₂ - in the presence of oxide hexafluorophosphate (HATU), and main ethylamine coupled with the following structure:

Producing a compound represented by:
(11) The product of step (10) is coupled with methyl 5-fluoro-2-nitrobenzoate in the presence of KCO _{3 in} hexamethylphosphoramide (HMPA) to give the structure

Producing a compound represented by:
(12) The product compound of step (11) is reduced in the presence of 10% Pd / C in methanol and hydrogen gas to give the following structure:

Producing a compound represented by:
(13) reacting the product of step (12) with N-chlorosuccinimide in CH ₃ CN to form the following structure:

Producing a compound represented by:
(14) The product compound of step (13) is reacted with NaNO ₂ , HBr and CuBr in CH ₃ CN to give the following structure:

Producing a compound represented by:
(15) The ester in the product compound of step (14) is reduced with LiBH ₄ in THF and MeOH to give the following structure:

Producing a compound represented by:
(16) The alcohol in the product compound of step (15) is reacted with MOM-Cl in the presence of N, N-diisopropylethylamine (DIEA) in THF to give the following structure:

Producing a compound represented by:
(17) The product of step (16) is prepared in 1,4-dioxane in the presence of PdCl ₂ (dppf) -CH ₂ Cl ₂ and KOAc with the following structure:

Is reacted with a compound represented by the following structure:

Producing a compound represented by:
(18) reacting the product of step (17) with HCl in THF to give the following structure:

Producing a compound having:
The said manufacturing method including.